Caspase-2, the most evolutionarily conserved of mammalian caspases, is autoactivated by proximity-induced dimerization/oligomerization. It is activated rapidly in response to many apoptotic stimuli and shows some unusual properties, including its ability to localize to the nucleus. Despite this the primary function of caspase-2 has remained enigmatic as caspase-2 knockout (KO) mice develop normally and do not show any overt phenotype that would relate to an essential role of caspase-2 in apoptosis. Our recent studies with KO mice now suggest that caspase-2 acts as a suppressor of tumourigenesis in some mouse models of cancer. Loss of caspase-2 enhances oncogene-mediated cell transformation and augments lymphomagenesis in EμMyc and Atm KO mouse models (1, 2). Further studies indicate that caspase-2 has a role in maintaining genome integrity as assessed by the extent of DNA damage and chromosomal aberrations in caspase-2-deficient tumour cells. Furthermore, cytogenetic analyses suggest that caspase-2 loss results in increased frequency of aneuploidy in tumours and in MEFs over time in culture. Perhaps because of the sensitised background, caspase-2 mice also show early hair greying, increased bone loss, increased oxidative stress-induced damage and reduced activities of antioxidant enzymes in the liver. We also found that caspase-2-deficiency results in a misregulation of age-related changes in the proteome. Taken together, our data suggest that caspase-2 is required for maintaining genomic integrity, and increased DNA damage and oxidative stress associated with caspase-2 deficiency are likely factors leading to enhanced potential for tumorigenesis in mice when challenged by additional oncogenic lesions.