Rescue Me revolves around the lives of the men in a New York City firehouse, the crew of 62 Truck. Examining the fraternal nature and relationships of firefighters, the series tackles the daily drama of the life-and-death situations associated with being a firefighter, while exploring the ways the men use dark humor to protect their true emotions.

At the start of the fifth season, Tommy finds himself in a relationship with Valerie that has already burned out, with a hole in his life where his emotionally inaccessible father used to be, and facing a possible expulsion from the firehouse for reckless behavior on the job. Nevertheless, Tommy's grasp on his sobriety appears firm and his dedication to a greater good unswerving.

However, when a foreign reporter brings an international perspective and a collection of 9/11 footage to the firehouse, things begin to unravel. Soon, neither Mickey's words of wisdom, nor the constant prodding of the young man he is attempting to sponsor can keep Tommy from slipping off the wagon. To make matters worse, Tommy must navigate \"no-strings-attached\" relationships with Sheila and Janet both of whom have hidden agendas. Meanwhile, with Katy off at boarding school and Colleen out of the house and living with Black Shawn, Janet begins dating a new man who pushes life and Tommy to their limits.

Franco takes up boxing as a way to vent his frustrations with the official story of 9/11. In the gym, Franco may have finally met his match when he falls for a hard-nosed female boxer. But when the rest of the crew finds reason to question Carla's sexuality, Franco discovers that his toughest bouts will be outside the ring.

The guys convince Mike to use his inheritance to buy a bar. After a rocky start, Mike's bar becomes a hotbed for debauchery and a venue to facilitate Mike's quest to become a rock star. Money, chicks, and booze - things couldn't be going any better until a rag-tag pack of outsiders infiltrate the premises and put a halt to the festivities.

When Tommy disapproves of Lou's motivations for his newfound interest in writing, Lou calls into question Tommy's fundamental values as a friend. Tommy's skepticism grows when Candy, the prostitute who ripped him off in season two, returns and attempts to re-ignite an old flame in Lou.

Sean is suffering back pain, which turns out to be more serious than he expected. His mother and brother show up to provide emotional support, but Sean must tackle the financial burden on his own. When he is finally well enough to leave the hospital, the guys find out that Sean's liver is not the only part of his body that has been affected by the ordeal.

Tommy's nephew Damian finishes school and is ushered into the firehouse as the new probie. When Tommy reluctantly takes Damian under his wing at Sheila's request, he puts the rest of the crew in harm's way. This dynamic quickly wears thin on both Needles and Feinberg, but Needles ultimately takes the firmer stance. From Tommy to Mike to Lou, everyone has a hand in Damian's mentorship.