Checkpoint kinase 2 (Chk2) is emerging as a key mediator of diverse cellular responses to genotoxic stress, guarding the integrity of the genome throughout eukaryotic evolution. Recent studies show the fundamental role of Chk2 in the network of genome-surveillance pathways that coordinate cell-cycle progression with DNA repair and cell survival or death. Defects in Chk2 contribute to the development of both hereditary and sporadic human cancers, and earmark this kinase as a candidate tumour suppressor and an attractive target for drug discovery.