The events of the game begin shortly before the events of Tom Clancy's Rainbow Six 3: Raven Shield. Bishop leads his/her team on a botched hostage rescue operation in Píc des Pyreneés, France in which a Rainbow hostage negotiator is killed due to one of his/her team members, Gabriel Nowak, defying orders by opening fire before additional Rainbow operatives arrive.
After securing the hostages, Bishop's team covers Nowak while he defuses a nearby bomb. Nowak is injured during a brief firefight shortly afterward and verbally lashes out at Bishop, taking out his apparent shame and anger on the team. Alpha Team, led by Domingo "Ding" Chavez, arrives and quell the situation. Nowak is rescued.
The game then moves forward to 2010 in Las Vegas, with Bishop commanding a new team on a mission in Las Vegas, Nevada. The National Security Agency (NSA) suspects two coyotes, Miguel and Alvarez Cabreros, of smuggling chemical weapons from Mexico into Las Vegas. The Cabreros are alerted when they discover and kill an undercover agent from the NSA, forcing Bishop’s team to rush to the warehouse containing the weapons. The team is delayed by a hostage situation that Bishop declares to be of top priority. During the ensuing rescue operation, the NSA informs a van possibly containing explosives has fled the scene.
Following the rescue, Bishop learns that in addition to a chemical bomb there is a conventional explosive device. The team locates the escaped chemical weapons van but turns up nothing. They frantically search the area but reach the target, a Las Vegas recreational center and sports complex, too late. The chemical weapon is detonated, and many innocent lives are lost.
Immediately afterward, Bishop's team learns that the younger Cabrero brother, Miguel, has escaped the area. Bishop's team gives chase, cornering and interrogating him in the Neon Boneyard. At first, Miguel denies any knowledge of the bomb, but after the team threatens him he confesses the location of the second bomb. Miguel then draws a weapon on the team and Bishop is forced to kill him. It is heavily implied during this scene that Bishop antagonizes Miguel into drawing his weapon, allowing Bishop to shoot him without any repercussions from the agency.
As Miguel told Bishop that the second bomb is on its way to the (fictional) Vegas Convention Center, the team redeploys to the center quickly, fighting through the huge building to find the chief of security being held by Alvarez Cabrero. The chief is wired up with explosives to kill him and deny the NSA evidence that he could leak. Upon defusing this device, Bishop learns that the second bomb is located on a monorail headed towards the hotel area. Bishop's team fights their way to the bomb and disables its timer, but they are unable to disable the bomb's remote detonation circuitry in a timely manner. Thinking quickly, Bishop suggests detonating the bomb themselves in an unpopulated area after sending it to a safe distance by activating the train. At this point, Bishop is contacted by a NSA agent, who tells him/her that the terrorists have set up in a Las Vegas penthouse and are preparing another attack.
As Bishop's team nears the penthouse, a sniper injures Sharon Judd, despite assurances by the NSA agent of a safe landing zone; fast-roping to the penthouse, the team proceeds to clear the building. Echo Team is deployed to take the other side of the building but are killed in a large explosion as Bishop's Bravo Team pushes forward, revealing the entire assault to be an ambush.
After rappelling from the penthouse to the casino below and fighting through more terrorists, Bishop learns that there is a third bomb held in a Chinese theater. The team assaults the theater and successfully defuses the bomb and saving several hostages. The team escapes and fights their way to the roof and is extracted once the roof is clear. Mike and Jung are then ordered to assist Logan in cleaning up Las Vegas following his team's ambush.
On the roof the NSA agent, wearing a balaclava, joins Bishop in the helicopter, saying that Alvarez Cabrero has been spotted at an airstrip in the desert. Bishop and the NSA agent enter the area at separate locations, and Bishop fights his/her way through an oil refinery and abandoned train-yard in order to get closer to the airstrip. When Bishop arrives, he/she discovers the NSA agent speaking with Cabrero. The agent is revealed to be Gabriel Nowak, who shoots and kills Alvarez. Nowak then insults Bishop, implying involvement in all of the team's recent troubles, before terrorists appear and attack. Bishop attempts to defend himself/herself but is knocked unconscious by an exploding airplane that he/she is hiding by. Bishop regains consciousness, having been dragged to safety by Gary Kenyon (the helicopter pilot), and reports to Ding. The latter orders him to stand down.
Bishop and Bravo Team, defying orders to stand down, follow Gabriel to a Costa Rican villa. As Bravo Team storms the complex, Nowak taunts Bishop and reveals that he was going to sell information about Rainbow operatives and their families to terrorists and criminals. Bishop closes in and attempts to face Gabriel alone; however, an attack helicopter and support troops arrive. Bishop manages to trick the helicopter into radioing for assistance, and Joanna Torres, Keller's intelligence officer, manages to triangulate the chopper based on its radio signal, eventually shooting it down with a SAM battery.
Gabriel and Bishop finally meet face to face. Gabriel gloats, claiming that he has outsmarted all of Rainbow and arguing that Bishop should have let him fix his own mistakes, including what happened in France, while Bishop tries to calm him down. Nowak eventually draws his weapon, and Bishop is forced to defend himself/herself, shooting Nowak as the rest of Bishop's team arrive from the other side. Bishop is berated by Chavez for disobeying orders, but is offered a position as deputy director of Rainbow at Rainbow HQ, Hereford, England.