The induction of apoptosis of virus-infected cells is an important defense mechanism of the host. Apoptosis of an infected cell can be induced cell autonomously as a consequence of viral replication or can be mediated by CTLs attacking the infected cells. Herpesviruses have developed different strategies to interfere with cell-autonomous apoptosis and to block CTL-induced apoptosis mediated by death receptors such as Fas and TRAIL. Herpesviruses, which establish a lifelong persistence in the infected host, can be found principally in two different conditions, episomal persistence with a limited number of genes expressed and lytic replication with expression of almost all genes. To meet the need of the virus to enhance survival of the infected cell, herpesviruses have evolved different strategies that function during both episomal persistence and lytic replication. Herpesviruses, which encode 70 to more than 200 genes have incorporated cell homologous antiapoptotic genes, they code for multifunctional genes that can also regulate apoptosis, and, finally, they modulate the expression of cellular apoptosis-regulating genes to favor survival of the infected cells. Viral interference with host cell apoptosis enhances viral replication, facilitates virus spread and persistence, and may promote the development of virus-induced cancer.