Cellular BCL-2-related proteins (cBCL-2s) function as regulators of programmed cell death (apoptosis), in part by modulating the release of proapoptotic signaling molecules from mitochondria. These factors act to promote activation of cysteine proteases of the caspase family and thereby propagate signaling of apoptotic cell death. DNA viruses are known to encode homologs of cellular antiapoptotic BCL-2 proteins (vBCL-2s), and the role of vBCL-2s in various aspects of viral infection and the mechanism by which they function have been gradually emerging. It is now apparent that inhibition of apoptosis by vBCL-2s in infected cells can prevent premature death of the host cell, which would impair virus production; can enable efficient emergence from latency; can facilitate persistent infection; and contributes to the avoidance of immune surveillance by the host. Thus, apoptosis is clearly a mechanism used by the host immune system and the infected host cell itself as part of the antiviral response. Deregulation of this delicate host–pathogen interaction can alter the course of virus replication, which may explain aspects of viral disease. Recent evidence suggests that vBCL-2s may target the core cellular proapoptotic machinery for inhibition, perhaps to secure a broad spectrum of apoptosis inhibition to the infected cell. Furthermore, because vBCL-2 family members and some of their cellular counterparts are oncogenic, deciphering their mode of action may be useful in understanding and thwarting human cancer. In this review we outline the role and the mechanism of action of vBCL-2 proteins in infected cells and how and why their function may be distinct from some of their cellular homologs.