Viruses have evolved numerous mechanisms to evade the host immune system and one of the strategies developed by HIV is to activate apoptotic programmes that destroy immune effectors. Not only does the HIV genome encode pro-apoptotic proteins, which kill both infected and uninfected lymphocytes through either members of the tumour-necrosis factor family or the mitochondrial pathway, but it also creates a state of chronic immune activation that is responsible for the exacerbation of physiological mechanisms of clonal deletion. This review discusses the molecular mechanisms by which HIV manipulates the apoptotic machinery to its advantage, assesses the functional consequences of this process and evaluates how new therapeutics might counteract this strategy.