Apoptosis mediated by the proapoptotic BCL-2 family members BCL-2-associated X-protein (BAX) and BCL-2 antagonist/killer (BAK) is part of the antiviral response at the cellular level to limit virus replication. Viruses, in turn, have evolved to encode antiapoptotic BCL-2 homologs (v-BCL-2s) to prevent the premature death of the infected host cell to sustain virus replication. These same v-BCL-2 proteins cooperate with loss of retinoblastoma protein and p53 tumor suppressor function, by inactivating the BAX and BAK apoptotic pathway to promote epithelial solid tumor growth and resistance to chemotherapy. Analogously to infected cells, failure of apoptosis in tumors permits the survival of abnormal, damaged cells displaying chromosome instability that may further promote tumor progression. Thus, both infected cells and tumor cells require inhibition of the apoptotic host defense mechanism, the insights from which can be exploited for therapy development.