Cytotoxic T lymphocyte and natural killer cell-initiated cell death is one of the primary mechanisms used by higher organisms to eliminate viruses and transformed cells. In this context, target cell death is rapid and efficient and initiated via two main pathways, involving either the ligation of death receptors or through the granule-exocytosis pathway. The granule-exocytosis pathway has attracted much attention over the past 10 years and consequently, a mechanism for granule-dependent killing has become reasonably well established. In the granule-dependent pathway, several proteolytic enzymes called granzymes are delivered to the target cell, promoting the activation of a family of death-inducing proteases called caspases. If caspases are inhibited by viral proteins or are inactivated through mutation, granzyme-mediated proteolysis of other cellular substrates ensures the timely death of infected or transformed cells. Here, we examine the findings that have shaped our current understanding of the mechanics of granule-dependent killing and discuss recent insights that have clarified some long-standing discrepancies in the granzyme literature.