The combination of immunization strategies with gene therapy methods constitutes a powerful tool for the purpose of genetic immunization. The cutaneous microenvironment, rich in professional antigen-presenting cells and accessory cells capable of initiating and controlling the intensity of specific immune responses, makes the skin a unique target for the expression of transgenic antigens. The fact that epidermal and dermal dendritic cells can be directly transfected using genetically engineered vectors allows in vivo manipulation of immune responses by modifying the function of these distinctive antigen-presenting cell populations. Importantly, coexpression of antigenic proteins together with immunostimulatory molecules, and/or adjuvant or leader sequences, makes possible the engineering of antigen-specific immune responses. Even though most of the mechanisms related to DNA immunization remain to be explored, the skin has emerged as an ideal target for evolving genetic vaccination techniques.