The E1A gene of human adenovirus (Ad) serotypes 2 and 5 induces susceptibility of cells from several species, including human, to lysis by natural killer cells, activated macrophages and a variety of other immunologic and nonimmune cellular injuries. This E1A activity is the rationale behind some treatment strategies using combined adenoviral vector infection and chemotherapy for cancer. This review will consider the evolution of the studies that have resulted in the current understanding of the cellular mechanisms of E1A-induced tumor cell cytolytic susceptibility and sensitization to apoptotic injury. The translation of in vitro observations to experimental models testing E1A-induced tumor rejection in the context of the cellular immune response and E1A-induced sensitization of human tumor cells to therapeutic injuries will be discussed. Review of available information on the molecular mechanisms of E1A-induced cellular sensitivity to immune and nonimmune injuries will be used as a basis for consideration of possible future directions of this research.