Selective decontamination of the digestive tract (SDD), an infection-control strategy designed to prevent nosocomial pneumonia in mechanically ventilated patients, has been implemented in numerous studies for more than 2 decades, but its role remains controversial. Sentinel studies in the 1960s and 1970s identified a link between colonization of the upper respiratory tract and subsequent increased risk of developing nosocomial pneumonia in critically ill patients. Studies in the 1980s found that prophylaxis with topical and systemic antibiotics to decontamination of the upper respiratory tract and gastrointestinal tract (particularly depleting gram-negative aerobic bacteria) was associated with lower rates of infections. However, impact on survival was not substantiated. However, several recent studies (including randomized trials and meta-analyses) suggest that SDD may improve survival in selected cohorts of critically ill patients in intensive care units (ICUs). Because liberal use of SDD (or any antimicrobial prophylactic strategy) may lead to escalating antimicrobial resistance, the risk of resistance varies according to local pathogens and resistance patterns. This review describes the development of the SDD concept, discusses recently published trials, and develops points for discussion and research. Additional studies are required to further define appropriate indications and limitations of this preventative strategy.