•  Caspase function •  Caspase‐2: Initiator or executioner caspase? •  Functions of caspase‐2 ‐  Role in development ‐  Caspase‐2 in aging ‐  Caspase‐2 is a tumour suppressor ‐  Caspase‐2 substrates •  Measuring caspase‐2 activation during apoptosis •  Caspase‐2 activation platforms •  Regulation of caspase‐2 activation ‐  Inhibition of caspase‐2 by Hsp90α ‐  Caspase‐2 activity is suppressed by phosphorylation at distinct sites ‐  Alternatively spliced isoforms of caspase‐2 ‐  Regulation of caspase‐2 during cell‐cycle •  Caspase‐2 in disease ‐  Cancer ‐  Neurodegenerative disorders ‐  Ischemia‐reperfusion Injury •  Concluding remarks Caspase‐2 is the most evolutionarily conserved of all the caspases, yet it has a poorly defined role in apoptotic pathways. This is mainly due to a dearth of techniques to determine the activation status of caspase‐2 and the lack of an abnormal phenotype in caspase‐2 deficient mice. Nevertheless, emerging evidence suggests that caspase‐2 may have important functions in a number of stress‐induced cell death pathways, in cell cycle maintenance and regulation of tumour progression. This review discusses recent advances that have been made to help elucidate the true role of this elusive caspase and the potential contribution of caspase‐2 to the pathology of human diseases including cancer.