The cytotoxic cell granule secretory pathway is viewed as indispensable for eliminating tumor and virally infected cells through a process in which the pore-forming protein, perforin, delivers the serine protease granzymes into cells targeted for destruction. Residing in cytotoxic cells, granzymes were originally anticipated to act both extracellularly and intracellularly. With the discovery that isolated granzymes induce apoptosis when combined with perforin, the broader functionality of the granzymes became unattractive. The purpose of this article is to describe observations indicating that granzymes possess non-cytotoxic activities that might include such diverse biologic effects as stimulation of pro-inflammatory cytokines, remodeling of extracellular matrices and inactivation of intracellular pathogens.