Protein phosphatase type 2A (PP2A) is a major Ser/Thr phosphatase involved in several cellular signal transduction pathways. In this review, we will focus on recent progress concerning the role of PP2A in apoptotic signalling. Since PP2A activates pro-apoptotic and inhibits anti-apoptotic proteins of the Bcl-2 family, we conclude that PP2A has a positive regulatory function in apoptosis. However, in Drosophila, a specific subset of the PP2A holoenzyme family, containing B′/PR61 as third regulatory subunit, is inhibitory for apoptosis, suggesting different regulatory mechanisms and substrates in different species. Moreover, PP2A acts not only upstream as a regulator of the apoptotic signal transduction pathway but also downstream as a substrate of effector caspases. Hence, PP2A is involved in the regulation as well as in the cellular response of apoptosis. Probably, various PP2A holoenzymes with distinct regulatory subunits specifically target different apoptotic substrates. This could explain the implication of PP2A at several levels of the apoptotic signal transduction pathway. Finally, some viral proteins such as adenovirus E4orf4 and simian virus small t target PP2A to alter its activity, resulting in induction of apoptosis as a regulatory mechanism to enhance virus spread.