DNA vaccines use eukaryotic expression vectors to produce immunizing proteins in the vaccinated host. Popular methods of delivery are intramuscular and intradermal saline injections of DNA and gene gun bombardment of skin with DNA-coated gold beads. The method of DNA inoculation (gene gun versus intramuscular injection) and the form of the DNA-expressed antigen (cell-associated versus secreted) determine whether T-cell help will be primarily type 1 or type 2. Mechanistically, gene gun-delivered DNA initiates responses by transfected or antigen-bearing epidermal Langerhans cells that move in lymph from bombarded skin to the draining lymph nodes. Following i.m. injections, the functional DNA appears to move as free DNA through blood to the spleen where professional antigen presenting cells initiate responses. Preclinical trials with DNA vaccines have had outstanding success. DNA-based immunizations have provided protection against viral, bacterial and parasitic diseases, modulated the effects of autoimmune and allergic disease, and provided some hope for the control of cancer.