Caspase-2, the most evolutionarily conserved member of the caspase family, has redundant function in cell death during development. Surprisingly, our recent work implicates caspase-2 in tumour suppression. Using multiple murine models we found that loss of caspase-2 enhances tumourigenesis in several cancer types. In all cases where loss of caspase-2 was associated with increased tumour burden we observed that caspase-2-deficiency results in enhanced chromosomal instability (CIN) and aneuploidy. Similarly, increased CIN and aneuploidy were characteristics of caspase-2-deficient mouse embryonic fibroblasts in culture as well as human tumour cells with CASP2 gene knockout. Using an engineered mouse lacking the catalytic activity of caspase-2 (Casp2C320S mutant mouse) we found that caspase-2 enzyme activity is essential for its function in limiting aneuploidy. Caspase-2 was activated in cells following CIN and using live cell imaging we found that caspase-2 is required for apoptotic deletion of cells carrying mitotic defects. Thus apoptotic activity of caspase-2 is necessary for deleting cells with CIN to limit aneuploidy and we propose that this is linked to the tumour suppressor function of caspase-2. In an additional model the Villunger laboratory has proposed that in response of cytokinesis failure caspase-2-mediated cleavage of Mdm2 and resulting p53 stabilization induces cell cycle arrest, thus preventing polyploidy. It is therefore possible that caspase-2 is involved in two checkpoints, one leading to apoptosis of cells with CIN and the other, cell cycle arrest following cytokinesis failure. Caspase-2 is apparently activated in a Piddosome-dependent manner in response to cytokinesis failure. We are now investigating how caspase-2 senses mitotic errors and becomes activated and how is such activation regulated.