RNA interference (RNAi) is a powerful research tool that can be used to turn off-or silence-the expression of a specific gene. In recent years, RNAi screening on a genome-wide scale has provided the opportunity to identify factors and pathways involved in complex biological processes in a systematic and unbiased manner. Here we describe a genome-wide RNAi screening strategy to identify genes that are required for a particular type of cellular senescence called oncogene-induced senescence. The approach we describe is a general screening strategy that can be applied to the study of other forms of cellular senescence, including replicative senescence. © Springer Science+Business Media New York 2013.