Cytotoxic T lymphocytes (CTLs) search out and destroy pathogenic cells, such as those infected with viruses. The biochemistry laboratory at the University of Alberta (Edmonton, Alta.) studies the molecular mechanisms used by these effectors, and this review covers research on this topic primarily from this group. Research there began with the discovery of the granzyme genes and the realization that granzyme B (GrB) had an unusual substrate specificity. Cleavage at aspartate residues gave us the clue that caspases, key regulators of apoptosis, were important substrates. However, it is now clear that mitochondria are also important in controlling granzyme-induced apoptosis. This led to the discovery that the proapoptotic member of the Bcl2 family, Bid, is also activated by GrB. Cleaved Bid then translocates to the mitochondria, resulting in the release of antagonists of inhibitors of apoptosis proteins. The evolution of our understanding of the molecular basis of CTL killing is presented.