The player begins the game as newly appointed Rainbow team leader Logan Keller, with two squad mates, Gabriel Nowak and Kan Akahashi, on a mission in a Mexican border town called San Joshua del Mosquiera in the year 2010. The player also has various skills, such as the ability to rappel up and down buildings while shooting and the ability to fast rope into an area. Most important was the developers' decision to remove the mission planning feature. The developers have also opted to not include any cutscenes, instead telling the story through video feeds played through the heads-up display, similar to Ghost Recon Advanced Warfighter. The game has also been noted for rectifying the artificial intelligence for squad members, a problematic gameplay element that afflicted previous games in the series, alongside Ghost Recon Advanced Warfighter 2. The player can also give voice commands using the Xbox 360 headset, but team-mates are no longer audible through the headset. This command system was borrowed from another Ubisoft game, Tom Clancy's Ghost Recon Advanced Warfighter. Other changes include a larger enemy presence and much tougher artificial intelligence, a shift in focus to where kills will be much harder to obtain, a reincarnated aiming system similar to the aiming system of the old Rainbow Six games and Call of Duty, a context-sensitive D-pad based command system for the player's squad and sections of game play where the player will scale buildings and cause environmental damage.

Furthermore, a third-person view has been included for moments where players can blind-fire around corners to lay down suppression or covering fire.

The player's vision is also greatly impaired while damaged, similar to the health system in Gears of War. However, the regeneration is slow in comparison to other games if the player does not move to cover quickly enough, one or two more bullets will lead to death. Rainbow Six Vegas changes the series with multiple new features, such as a new health system where the player regenerates health while not taking fire (it should be noted that the player may sometimes be killed instantly, without a chance to regenerate health this usually happens from grenades, as well as taking close range fire from very powerful weapons, particularly to the head).

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