Under many circumstances, prophylactic immunizations are considered as the only possible strategy to control infectious diseases. Considerable efforts are typically invested in immunogen selection but, erroneously, the route of administration is not usually a major concern despite the fact that it can strongly influence efficacy. The skin is now considered a key component of the lymphatic system with tremendous potential as a target for vaccination. The purpose of this review is to present the immunological basis of the skin-associated lymphoid tissue, so as to provide understanding of the skin vaccination strategies. Several strategies are currently being developed for the transcutaneous delivery of antigens. The classical, mechanical or chemical disruptions versus the newest approaches based on microneedles for antigen delivery through the skin are discussed herein.