The effective vaccines developed against a variety of infectious agents, including polio, measles, and hepatitis B, represent major achievements in medicine. These vaccines, usually composed of microbial antigens, are often associated with an adjuvant that activates dendritic cells (DCs). Many infectious diseases are still in need of an effective vaccine including HIV, malaria, hepatitis C, and tuberculosis. In some cases, the induction of cellular rather than humoral responses may be more important because the goal is to control and eliminate the existing infection rather than to prevent it. Our increased understanding of the mechanisms of antigen presentation, particularly with the description of DC subsets with distinct functions, as well as their plasticity in responding to extrinsic signals, represent opportunities to develop novel vaccines. In addition, we foresee that this increased knowledge will permit us to design vaccines that will reprogram the immune system to intervene therapeutically in cancer, allergy, and autoimmunity.