Story: After the initial Chernobyl Disaster, attempts were made to repopulate the area, primarily with scientists and military personnel. However, in 2006, almost 20 years after the first incident, a second disaster occurred, caused by the C-consciousness (rus. "О-Сознание" which corresponds with "осознание" - "realisation, awareness", ukr. "О-свідомлення") program, killing or mutating most of the inhabitants.

S.T.A.L.K.E.R. begins years later, after people have begun coming to the zone in search of money, valuable artifacts, and scientific information.

S.T.A.L.K.E.R. takes place in an area called "The Zone", which is based on the real-life Chernobyl Exclusion Zone and partly on the settings of the source novel and film. It encompasses roughly 30 square kilometers and features a slice of Chernobyl extending south from Chernobyl Nuclear Power Plant; geographical changes for artistic license include moving the city of Pripyat into this area (it is actually to the north-west of the power station), although the city itself is directly modeled on its real-life counterpart, albeit smaller in size