Genetic immunization has been widely applied in efforts to find novel and efficient mechanisms of stimulating the immune response. An effective attack against viral pathogens or tumors often requires activation of T cell-mediated immunity and the generation of cytotoxic T cells. Intramuscular immunization with plasmid DNA containing cDNAs that encode proteins results in expression and secretion of the foreign antigen by muscle cells. T cell activation occurs when peptide fragments of the exogenous protein are presented by major histocompatibility complex class I molecules on the surface of professional antigen-presenting cells. Identification of specific peptide epitopes from a protein antigen presented to T cells during an infectious process or tumor situation would provide all of the antigenic information needed to stimulate effective T cell-mediated immunity. Such peptides represent the naturally processed epitopes selected by the processing machinery of antigen presenting cells. Delivery of this information to the appropriate cells in vivo might be sufficient to stimulate T cell immunity and overcome the difficulties associated with overexpression of large protein antigens or those with potentially toxic side effects. This report describes the use of naturally processed T cell epitopes, administered in plasmid DNA vaccines, to stimulate cytotoxic T cell responses to two viral antigens effectively.