Starting out fresh, Mike puts some distance between himself and Marcellus, grieves over Grizz's transfer to New Orleans, and moves into a new house, where he meets his energetic new neighbor, Liz Garza, who turns out to be an ex-nun turned probation officer; Jamie Farrell, a young man with a troubled past who isn't quite what he seems, enlists Mike's help after he witnesses a quadruple murder and is pursued by the D.E.A. agents who committed the crime; Mike seeks out Marcellus for information, and is warned to steer clear; risking his career, Marcellus saves Mike and Jaime from certain death at the hand of the agents; faced with a serious illness, Marcellus reaches out for Mike's friendship.
Mike and Marcellus work together to free an innocent man caught up in the nightmare of being falsely accused of terrorism by an F.B.I. agent who runs amok under the cover of the so-called ""Patriot"" Act when bombs go off at the Criminal Justice Center; in a misguided attempt to help, Jaime uses Mike's computer to hack into the F.B.I.'s database, which only leads to landing Mike in custody as well; Mike uses his time in custody to figure out that the bombings might be personal rather than institutional attacks, and gives Jaime the opportunity to redeem himself by having him hack into the PPD's database to find the link between the victims, who ends up being an ex-con out to destroy the people responsible for putting him behind bars; Mike and Marcellus track the bomber down just in time to prevent him from harming the next victim on his list, his probation officer, who turns out to be Mike's neighbor Liz.
Bettina's client Brian is released on a technicality after being accused of murder, and he seeks Mike's help in finding out who actually committed the crime so that his name and reputation can be restored; Marcellus undergoes surgery and gets good news from his doctor and a rebuke from Deborah for keeping his condition hidden; Liz helps Brian find a job and place to live when his employer and his wife abandon him; Jamie uses his street skills and some fast talking to provide Mike with an impressive vehicle in his search for information to support Brian's story; when he unearths information about the victim which reveals that she and her family were not who they appeared to be, Mike traps the murderer and clears Brian's name; as Mike arrives to take him home from the hospital, Marcellus is shot by a man posing as an orderly.
While Mike identifies the man who shot Marcellus as someone who escaped from a drug dealer take-down long ago, a second attempt on Marcellus's life points to the possibility of two different shooters; forced to hide out from some bad guys, Jamie temporarily moves in with Mike, and Liz teaches him how to be a good neighbor.
After Mike saves Leda Mills from three would-be rapists, she decides that the only way she can regain control of her life and prevent her attackers from hurting other women is to hunt them down and murder them; Marcellus helps a teenager being neglected and corrupted by his drug-addicted father; Mike is horrified when Leda phones him after the first murder to thank him for being her inspiration, and works with Marcellus to stop her killing spree, but it's Liz's insights into her behavior that give them the key to her capture.
Mike helps an amnesiac regain her memory to uncover who has marked her for murder; working with Mike, Jaime uncovers her unsavory past, but not before Mike falls for her; Jamie pretends to be Marcellus to impress a girl he meets online, and Marcellus goes along with it, in exchange for Jamie's painting his kitchen.
On the anniversary of his brother Rick's death, Jamie decides to meet with his father, Richard Farrel, in an attempt at reconciliation and instead discovers his affair with a young woman named Cate Rawlings, who is later found murdered; at Jaime's request, Mike attempts to find out what evidence Marcellus has on the murder without revealing Richard's affair with Cate; after Jamie breaks into Cate's apartment to remove evidence implicating his father, he's arrested and unwittingly gives Marcellus the information he needs to charge Richard with the crime; even though Marcellus is angry that Mike deceived him about Richard, the former partners work together to uncover the evidence that clears Richard of the crime; Jaime is devastated when Richard rejects his efforts at reconciliation once his name is cleared.
A young girl who witnessed a murder seeks Mike's help in helping her evade the corrupt police officer who has been paid off to cover up the crime and silence her; Marcellus takes up residence on Mike's sofa as his marital problems continue.
While Mike is more than willing to assist Jamie in turning a teenage friend away from prostitution, Liz is much less sympathetic to her plight until Jamie convinces her that the privileged upbringing he and the girl shared is no protection against pain; continuing to mentor Cal, Marcellus strikes a bargain with a loan shark to arrest his competition on the street in exchange for his releasing Cal from his crew; Mike walks on eggshells in the face of Liz's anger; after Liz manages to get Cal out of the shelter and into a foster home, Deborah agrees to let him stay at the Washington house until his foster placement goes through even though things are very much strained between her and Marcellus; Mike, Marcellus and Liz use their individual talents to get Jamie's friend out of the hands of her pimp and into the arms of her parents.
After Liz asks Mike to look into the death of the girlfriend of her fireman friend Nick, Mike comes into conflict with Nick's boss, who's an old nemesis; Marcellus works the case from a pattern-killing angle, linking it to a similar murder 2 years ago, and discovers that the otherwise unconnected victims had the same locksmith; Mike discovers that a fire that Nick's squad recently fought was in a building that housed a methadone lab where $112,600 disappeared, and suspicion points to the squad.
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After Jamie and his friend Wilson are jumped by gay-bashing thugs and the beat cops are reluctant to take the crime seriously, Mike enlists Marcellus's help in obtaining reports of other assaults in the area to determine if the cops are failing to report hate crimes properly; Marcellus becomes concerned about the future of his marriage when he learns that Deborah has been seeing another man; Wilson is murdered after he recognizes one of his attackers, and Mike finally uncovers why the beat cops were reluctant to file complete reports that could point out patterns in the gay-bashings in their district.
Mike steps in to help his cousin who's caught a downward spiral of addiction and suicidal urges as he combats post-traumatic stress after serving in Iraq.
Mike uncovers an illicit adoption ring trafficking in stolen babies when he grudgingly agrees to help one of Liz's clients, a former addict who's turned her life around, in the search for her missing child; Marcellus calls an end to it when he realizes that his obsession over the new man in Deborah's life has gone too far.
When Mike attempts to return the cell phone a stripper named Molly leaves in his cab and discovers that she's disappeared, he sets out to find her for the sake of Quinn, her twelve year old daughter; Marcellus's old friend and mentor Henry Baker asks his help in investigating how his jobless grandson Darryl has such an endless supply of cash; Quinn and Marcellus provide Mike with the inspiration and information he needs to find Molly, who's been kidnapped by one of the partners in the law firm where she works during the day as a paralegal; after Marcellus discovers that Darryl is linked to a series of high-end burglaries, he offers to sweep it under the rug, but Henry refuses to allow Marcellus to cover up the boy's crimes.
As Mike and his passenger exchange ""she done me wrong"" stories, he reminiscences about the time he almost fell for the charms of a greedy woman whose doctor lover deceived her husband into believing that he was dying. Marcellus arrests her lover for helping her husband arrange for a hitman so that his wife could collect on the double indemnity clause of his life insurance policy, but is unable to file charges on the woman both Mike and Marcellus believe was behind the entire plot.
When a drug dealer framed by Mike and Marcellus after they were unable to arrest him legitimately is released from prison, he begins to wield a path of destruction through Mike's life, endangering Liz and Jamie; Mike and Liz decide to move their relationship forward.