Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are indispensable factors in the body's ongoing defence against viral infection and tumor development. CTL/NK cells recognize and kill infected or abberant target cells by two major pathways: either through introduction of a battery of proteases–called granzymes–to the target cell cytosol, or through TNF superfamily-dependent killing. During granzyme-dependent killing, target cell death is quick and efficient and is mediated by multiple granzymes, acting via redundant cell death pathways. Although granzyme-mediated cell death has been intensively studied, recent work has also hinted at an alternative, proinflammatory role for these enzymes. Thus, in addition to their well-established role as intracellular effectors of target cell death, recent data suggest that granzymes may have an extracellular role in the propagation of immune signals. In this study, we discuss the role of granzymes as central factors in antitumor immunity, as well possible roles for these proteases as instigators of inflammation.