Baltimore Det. Jimmy McNulty finds himself in hot water with his superior Major William Rawls after a drug dealer, D'Angelo Barksdale who is charged with three murders, is acquitted. McNulty knows the judge in question and although it's not his case, he's called into chambers to explain what happened. Obviously key witnesses recanted their police statements on the stand but McNulty doesn't underplay Barksdale's role in at least 7 other murders. When the judge's raises his concerns at the senior levels of the police department, they have a new investigation on their hands. Lt. Cedric Daniels is put in charge with Kima Greggs as the lead detective. As for Barksdale, he finds himself demoted to a low-level dealer after his arrest and he obviously has to prove himself yet again.

Lt. Daniels puts his team together but the extra help he's asked includes several less than stellar officers. It also includes McNulty, who is obviously in the doghouse. When one of the witnesses against D'Angelo Barksdale is found dead, McNulty and his homicide partner 'Bunk' Moreland bring him in for questioning. They have no evidence that he had anything to do with the killing but their instincts tell them otherwise. When news of the witnesses death hits the press, Major Rawls is convinced that McNulty is again responsible. Three of the newly assigned detectives, Hec, Prez and Carver decide to go to the towers and flex a little muscle only to have it turn into a major disaster.

McNulty uses his children to tail Stringer after a chance encounter in a local market, with one of them getting his license plate. As the detail discuss the implications of the pit pay-phones being disconnected, speculating the crew are going to start using phones outside their immediate area of operations, Herc and Carver prepare for the sergeant's exam. Stinkum, Roland 'Wee-Bey' Brice (Hassan Johnson), and Savino Bratton (Chris Clanton) raid Omar's pad, but he is nowhere to be found. Avon is unhappy when he learns of Orlando's proposal to D'Angelo. Meanwhile, Greggs and Carver arrest a driver picking up a large amount of cash from the towers, but are surprised to learn he is an aide to State Senator Clay Davis (Isiah Whitlock Jr.). Burrell is furious with this turn of events and confronts Daniels about the direction in which the case is heading, giving him one week to charge Avon and/or Stringer. Phelan, however, tells Burrell he wants the full thirty days of surveillance assigned by the court. As Wee-Bey and Stinkum attempt to take over new territory, they encounter an unanticipated problem.

D'Angelo speaks to Wallace, who tells him he wants to go back to school and get out of the Game. However, Malik 'Poot' Carr (Tray Chaney) discovers Wallace has started using cocaine to help him deal with his guilt over Brandon's murder. Freamon gets Sydnor and Prez started on the complex Barksdale money trail, including possible political connections, and they are surprised to find Avon's corporations have been buying up vacant buildings in run-down parts of the city. Greggs and Freamon approach D'Angelo's girlfriend, Shardene Ennis (Wendy Grantham), who works at Orlando's, in the hopes they can turn her into a CI. After Bubbles narrowly avoids a beating whilst stealing a package that turns out to be stepped on, he decides to try to get clean. Avon and Eastside kingpin 'Proposition' Joe Stewart (Robert F. Chew) stage the annual East vs. West basketball game, but when the detail follows Avon afterwards, they get something they never expected. Meanwhile, having already killed Stinkum, Omar sets in motion a plan to gain revenge on Avon for Brandon's death.

Avon, Stringer and Wee-Bey discuss how best to deal with Omar after the attempted hit on Avon, deciding to let him think they want peace, whilst secretly planning to kill him. As such, Omar and Stringer meet for a parley, with security provided by Prop Joe. Meanwhile, Stringer insists on decreasing Avon's visibility in light of the detail's attempt to follow him after the basketball game. An irritable Phelan signs an affidavit for the new phone being used by the pit crew, and Pearlman tells McNulty that he is not up for automatic re-election, possibly because of the feathers he has ruffled due to his involvement with the Barksdale case. D'Angelo tries to understand why Shardene has left him, and after being clean for three days, Bubbles gets some advice from Waylon, before turning to Greggs for support. Meanwhile, McNulty attempts to flip Wallace, and the detail identifies Barksdale's main stash house. However, when Orlando's attempt to purchase weight gets him a lot more than he bargained for, Burrell sees an opportunity for a dangerous undercover operation.

While Greggs' life hangs in the balance, the entire department attempts to hunt down Savino. When Wallace flips, willing to testify that Stringer, Wee-Bey and Bird killed Brandon, Daniels stashes him in his grandmother's house on the outskirts of the city, but he soon becomes restless. Stringer tells Wee-Bey he needs to get out of Baltimore until the Savino investigation cools off, while Avon considers his next move. When McNulty and Pearlman try to pressure Levy into giving up Savino, he proves smarter than they gave him credit for. Meanwhile, when the detail's hand is forced, and a series of city-wide raids are ordered so as to appease Burrell's desire for "dope on the table," McNulty goes to see Phelan for help, but is surprised at his reaction. Daniels decides not to raid the main Barksdale stash house, but when word of his plan gets back to Burrell, he realizes there is a snitch in the detail. Elsewhere, Bubbles finds it increasingly difficult to stay clean.

Season Five premiere. As McNulty and the detail continue staking out Marlo's crew, recently promoted Sergeant Carver is welcomed by a cauldron of discontent from officers coping with unpaid overtime.

Mystified by Omar's disappearance, Marlo and Chris ramp up their efforts to locate their nemesis. After a sparsely attended waterfront ceremony, Carcetti fires away at a larger press event--and recasts himself as a champion for the homeless.

An unexpected call puts Templeton back in the spotlight--and gets McNulty more attention than he expected. Bunk bucks at Landsman when ordered to help with the force's most recent red ball.