The story picks up approximately three years after the season three finale. It's revealed that, during the narrative gap, Guido has been forced to work in Milan, and so he's constantly moving between the Lombardy capital and the Italian capital, having yet to secure a transfer to Rome. Libero and his three eldest grandchildren return from Australia, where they spent the summer with Lele, Alice, and their two younger grandchildren. Nicola returns to Italy to seek a divorce from Enrica. After some disagreement, she agrees to a consensual divorce and invests all her money in a business deal with her ex-husband, which, however, turns out to be a scam. Enrica thus becomes penniless and is taken in by the Martinis. Cettina and Torello move into the cottage next door to the Martinis', and Torello moves his funeral home into the new house.
There's a lot of news in the Martini household: Maria and Guido have been engaged for two years, and Guido travels back and forth between Rome and Milan. Ciccio still plays rugby and is engaged to an English girl named Emma and...
Grandpa Libero is called to school because Annuccia wrote a decidedly strange essay about family. Maria rents a house for herself and Guido, but discovers that, for now, he's forced to stay in Milan.
Meanwhile, Guido is sad because he has to stay in Milan for another two years and doesn't know how to tell Maria, who is currently interning at the local health authority. On the way to Milan, he has an accident.
Maria misses Guido greatly and is considering continuing her studies in Milan, at least until graduation. Guido, meanwhile, is trying every way to get a transfer, but it seems hopeless.
Cettina and Torello's house is now finished, but Cettina is in for some unpleasant surprises. Maria and Guido have decided to move in together, and to keep them from moving far away, Cettina finds an unexpected solution.
The family decides to give Guido and Maria a hot tub and a Bohemian crystal chandelier, but the children get angry because they want to furnish the house themselves. The first arguments arise.
Among friends and family, Guido and Maria can't find a moment of peace at home, and this certainly isn't good for the couple. Grandpa Libero, however, due to a series of misunderstandings, thinks Ciccio is taking drugs.
Grandpa Nicola makes a grand comeback, but the reality is very different from what he pretends. He invites Maria on a cruise, and she, who initially refuses, eventually realizes that all her grandfather has left is family affection.
While Marcello feels attracted to Eufrasia, Torello's nephew arrives in Rome, whom Cettina welcomes like a son.
Cettina asks Torello to bring his grandson Rosalbo into the partnership, but one night they overhear him plotting against them on the phone. The two decide to make life impossible.
Cettina doesn't know how to tell Torello that she's not actually pregnant because he's showering her with attention, arranging everything for the future baby. During an ultrasound, she steals a video showing triplets to play along.
Libero is worried about Olindo, an old friend of his who's been missing for days. He learns that he's in a nursing home and can't even talk to him or find out how he's doing. Libero then asks Guido to do an inspection.
Maria has returned from her cruise, and Guido immediately showers her with affection, so much so that the entire Martini family catches them soaking in the hot tub. Meanwhile, Cettina has a truly horrifying experience.
Guido is anxious because he has to present the project for the family hospital, but Maria forgets the interviews with the local health authority. But the troubles aren't over: her scooter doesn't work, and it's a race against time.
Reby tells the Martinis that she's getting married to a Japanese designer she met the week before. Maria isn't convinced, knowing her friend's quick crush, but this time it seems serious.
Guido finds a pregnancy test, actually belonging to Reby, and, frightened by something he feels is bigger than him, runs away and leaves a note for Maria. Having heard nothing from him for two days, Maria is heartbroken.
A man very similar to Grandpa Libero has been wandering around the Martini house for a few days, and trouble begins for Grandpa: everyone is starting to think he's seriously getting old and can't remember things.
After a check-up recommended by Enrica, Grandpa Libero learned that his blood pressure isn't good and that he might need open-heart surgery.
Libero writes a letter and gives it to Enrica, asking her to pass it on to Lele in case he dies. Then they both go to the town hall to sign the wedding papers and ask to get married as soon as possible.
The local health authority (ASL) is in danger of closing, and all the doctors organize a sit-in protest, which proves futile. Guido, however, decides to request a return to Milan, since staying in Rome no longer makes sense to him.
While the local health authority (ASL) is being dismantled, the doctors decide to perform all scheduled visits free of charge. Meanwhile, Guido is nervous and has an argument with Maria. Furthermore, he will be responsible for closing the local health authority (ASL) for good.
Franco decides to take Maria to a farm, but that same evening, after reading a note from Guido, Maria realizes she's confused. Fortunately, the only thing she's certain of is that she doesn't love Franco.
Guido is seeking funding for the family hospital and decides to organize a charity match to raise funds, while also offering a donation to the bank.
After spending the night with Guido, Maria runs away and confides in Reby, telling her friend what happened the night before. She also tells her that she's confused and doesn't know what she's feeling right now.
Guido and Maria are back together and are stronger and happier than before, but he doesn't want Maria to leave for Nigeria. He also has a very important proposal in store.
After three years away, Lele returns to the Martini household, finding the situation more than a little unsettling. Thanks to Grandpa Libero's help, Lele will finally be able to become a full-fledged family man again.
Guido is anxious because he has to present the project for the family hospital, but Maria forgets the interviews with the ASL. But the troubles aren't over: the scooter doesn't work, it's a race against time.
Reby tells the Martinis that she is getting married to a Japanese designer she met the week before. Maria is not convinced, knowing the fast falling in love with her friend, but this time it seems serious.
Guido finds a pregnancy test, actually belonging to Reby and, frightened by something he feels is bigger than him, he runs away and leaves himself a note for Maria. The girl, with no news from her for two days, is heartbroken.
A man very similar to grandfather Libero has been wandering around the Martini house for a few days and for grandfather trouble begins: everyone begins to think that he is seriously getting old and does not remember things.
After a check-up recommended by Enrica, grandfather Libero learned that his values ​​are not good and that open heart surgery may be necessary.
Libero writes a letter and delivers it to Enrica with the task of sending it to Lele in case he dies, then both go to the town hall to sign the marriage papers and ask to get married as soon as possible.
The ASL risks closing and all the doctors organize a protest sit-in, which will prove to be useless. Guido, on the other hand, decides to make a request to return to Milan, given that staying in Rome no longer makes sense for him.
While the ASL is being dismantled, the doctors decide to carry out all the visits on the list for free. Meanwhile Guido is nervous and has an argument with Maria. Furthermore, he will be responsible for definitively closing the ASL.
Franco decides to take Maria to a farmhouse, but the same evening the girl, after reading a note from Guido, realizes she is confused and luckily the only thing she is sure of is that she doesn't love Franco.
Guido is looking for funding for the family hospital and decides to organize a heart game to raise funds and at the same time proposes a donation to the bank.
After spending the night with Guido, Maria runs away and confides in Reby, telling her friend what happened the night before. But she also tells her that she's confused that she doesn't know what she's feeling right now.
Guido and Maria are back together and are stronger and happier than before, but he wishes Maria would not leave for Nigeria. He also has a really important proposal in store.
After three years of absence, Lele returns to the Martini house, finding a situation that is not a little indifferent. Thanks to the help of Nonno Libero, Lele will finally be able to become a full-fledged family man again.