During coevolution with their hosts, viruses have "learned" to intercept or to activate the principal signal transducing pathways leading to cell death. A number of proteins from pathophysiologically relevant viruses are targeted to mitochondria and regulate (induce or inhibit) the apoptosis-associated permeabilization of mitochondrial membranes. Such proteins are encoded by human immunodeficiency virus 1, Kaposi's sarcoma-associated herpesvirus, human T-cell leukemia virus-1, hepatitis B virus, cytomegalovirus, and Epstein Barr virus, among others. Within mitochondria, such apoptosis regulators from viral origin can target distinct proteins from the Bcl-2 family and the permeability transition pore complex including the adenine nucleotide translocase, cyclophilin D, the voltage-dependent anion channel, and the peripheral benzodiazepine receptor. Thus, viral proteins can regulate apoptosis at the mitochondrial level by acting on a variety of different targets.