Purines are ubiquitous endogenous metabolites, and their roles as signalling molecules, especially in the case of adenosine and ATP, are well documented. The release of purines is increased when cells are highly activated, stressed or damaged, and this is known to have profound effects on various organ systems. Recently, purines like adenosine and ATP have been shown to be cytotoxic. Current evidence suggests that adenosine induces cell death by apoptosis, whereas ATP appears to cause both necrosis and apoptosis. Apoptosis is an important physiological process during normal tissue turnover and in the maturation of the immune system, embryogenesis, metamorphosis, endocrine-dependent tissue atrophy, etc. Recently, many of the key components of the apoptotic cell death cascade have become unravelled. In particular, proteases belonging to the interleukin-1 beta-converting (ICE) enzyme family, also known as caspases, have been shown to act as an intracellular convergence point that orchestrates the morphological and biochemical features of apoptosis. However, little is known about the signalling or the biochemical mechanisms of purine-mediated cell death. Adenosine appears to act through P1 purinoceptors, although the subtype involved remains controversial, whereas ATP may involve both P2X1 and P2X7 purinoceptors. More recent evidence suggests that the intracellular levels of purines, in addition to the cell surface receptor-mediated responses, may also play a critical role by modulating other apoptotic cell death signals. Here, we review our current understanding about purines in mediating cell death and raise a number of questions as to the possible mechanisms involved.