Animal viruses permeabilize cells at two well-defined moments during infection: (1) early, when the virus gains access to the cytoplasm, and (2) during the expression of the virus genome. The molecular mechanisms underlying both events are clearly different; early membrane permeability is induced by isolated virus particles, whereas late membrane leakiness is produced by newly synthesized virus protein(s) that possess activities resembling ionophores or membrane-active toxins. Detailed knowledge of the mechanisms, by which animal viruses permeabilize cells, adds to our understanding of the steps involved in virus replication. Studies on early membrane permeabilization give clues about the processes underlying entry of animal viruses into cells; understanding gained on the modification by viral proteins of membrane permeability during virus replication indicates that membrane leakiness is required for efficient virus release from infected cells or virus budding, in the case of enveloped viruses. In addition, the activity of these membrane-active virus proteins may be related to virus interference with host cell metabolism and with the cytopathic effect that develops after virus infection.