Delivery of antigen in a manner that induces effective, antigen–specific immunity is a critical challenge in vaccine design. Optimal antigen presentation is mediated by professional antigen–presenting cells (APCs) capable of taking up, processing and presenting antigen to T cells in the context of costimulatory signals required for T–cell activation. Developing immunization strategies to optimize antigen presentation by dendritic cells, the most potent APCs, is a rational approach to vaccine design. Here we show that cutaneous genetic immunization with naked DNA results in potent, antigen–specific, cytotoxic T lymphocyte–mediated protective tumor immunity. This method of immunization results in the transfection of skin–derived dendritic cells, which localize in the draining lymph nodes. These observations provide a basis for further development of DNA–based vaccines and demonstrate the feasibility of genetically engineering dendritic cells in vivo.