FBI Special Agent Sarah Ashburn is a very skilled and effective investigator, but is despised by her fellow agents for her arrogance and condescending attitude. Hale, Ashburn's boss at the New York FBI field office who is being promoted, sends her to Boston to investigate a drug kingpin named Larkin with the promise that she would be considered as his replacement if she can solve the case while showing the ability to work effectively with others. Once in Boston, she is partnered with Shannon Mullins, a skilled but foulmouthed and rebellious police officer with the Boston Police Department. Ashburn's by-the-book philosophy clashes with Mullins' rugged and violent style of police work. Mullins discovers the details of the Larkin case by stealing the case file from Ashburn and insists on helping her. Ashburn reluctantly agrees, realizing that she needs Mullins' knowledge of the local area.
Ashburn and Mullins follow leads to a local night club owner and successfully place a bug on his cell phone. As they leave the club, Ashburn and Mullins are confronted by two DEA agents, Craig and Adam, who have been working the Larkin case for several months and are worried that their case will be compromised. After viewing him on a screen in the DEA agents' surveillance van, Ashburn discovers that Mullins' brother, Jason, was recently released from prison, having been put there by Mullins herself, and may be connected to Larkin's organization. Ashburn convinces Mullins to go to her parents' home to ask Jason for information on Larkin. On their arrival at the home, it becomes apparent that Mullins' parents and two other brothers still harbor deep resentment for Mullins' involvement in Jason's incarceration. Jason, who does not have any ill feelings toward his sister, tips her off about the body of a murdered drug dealer hidden in an abandoned car. Upon examination of the body, chemicals on the victim's shoes lead Ashburn and Mullins to an abandoned paint factory, where they witness a drug dealer being murdered by a member of Larkin's organization named Julian. The two apprehend Julian and interrogate him regarding Larkin, but are unable to extract any substantial information regarding Larkin's whereabouts.
The pair spends the evening in a bar bonding over several rounds of drinks. After a night of raucous drinking and partying, Ashburn wakes up the following morning to discover that, in her drunkenness, she has given her car keys to one of the bar patrons. After unsuccessfully pleading for the keys, Ashburn watches, along with Mullins, as the car explodes upon being started, having been fitted with a bomb. During the investigation of the explosion, the two discover that Julian has escaped from custody and may mean to harm Mullins' family. Mullins moves the family into a motel, but learns that Jason has joined with the Larkin organization in an attempt to aid the case. Jason gives her a tip about a drug shipment coming in to Boston Harbor. The FBI sets up a sting at the harbor to take down the shipment, but discovers that the ship they have been waiting for is actually only a pleasure cruise ship and Jason has been set up by Larkin. Knowing that he informed the FBI about the supposed drug shipment, Larkin attempts to have Jason killed, but only puts him into a coma.
Mullins vows to bring her brother's attacker to justice. Ashburn and Mullins learn of a warehouse where Larkin houses his operations. After equipping themselves with assault equipment from Mullins' extensive personal arsenal, the two infiltrate the warehouse. Despite taking out several of Larkin's men with a hand grenade, the two women are captured and bound by Julian, who threatens to torture them with knives. Julian is called away by Larkin, but before he leaves the room, he stabs Ashburn in the leg with one of the knives. Mullins removes the knife from Ashburn's leg and uses it to cut the rope binding her hands. Before she can finish freeing herself and Ashburn, they are discovered by Craig and Adam. Craig begins to untie the two women, but is shot and killed by Adam. Ashburn and Mullins deduce that Adam is actually Larkin, having been working his own case from inside the DEA for several months. Julian reenters and is instructed by Larkin to kill Ashburn and Mullins while he goes to the hospital to kill Jason. After Larkin leaves, Mullins, whose hands have already been untied, manages to finish freeing herself and Ashburn incapacitates Julian with a head butt. Mullins then frees Ashburn and the two race to the hospital to save Jason.
Upon their arrival, Mullins rushes to find Jason. Ashburn, hindered by the stab wound in her leg, is unable to move quickly. Mullins finds Jason's room, only to discover Larkin standing over his bed with a syringe, intending to kill Jason by injecting air into his vein, causing his death by an air embolism. Mullins drops her weapon in an attempt to save her brother's life. Ashburn, having had to crawl to the room, then enters and subdues Larkin by shooting him in the genitals. With Larkin captured, Ashburn requests to stay in the FBI's Boston field office, having developed a strong friendship with Mullins. Jason is shown having fully recovered from his coma. The film ends with Mullins receiving a commendation from the Boston Police Department, with her family present cheering for her, having reconciled with her.
Afterwards, following a misunderstanding earlier in the film, Mullins brings Ashburn her neighbor's cat, after believing that it was hers from a picture in her house.