Apoptin, a 13.6-kD protein encoded by chicken anemia virus, is paid more and more attention, since it selectively induces apoptosis in tumor cells while abolishes cytotoxic effect in normal cells. In addition, Apoptin shows different localization in tumor cells and normal cells: it predominantly accumulates in nucleus of tumor cells, whereas in normal cells, it is detected mainly in cytoplasm. There are various mechanisms implicated in the program of Apoptin-mediated cell death. Up to now, the interpretations have been recognized including that the particular domains control nucleocytoplasmic shuttling of Apoptin, phosphorylation on specific residue and varies relevant signaling contribute to Apoptin's activity, and the partners interacted with Apoptin regulate activity or subcellular localization of Apoptin. In this review, we make a comprehensive survey of the existing evidence about mechanisms of Apoptin's action, which might provide scientific basis to make progress in novel targeted tumor therapy.