Most vaccines are administered by intramuscular (i.m.) or subcutaneous (s.c.) routes, however, intradermal (i.d.) and transcutaneous (t.c.) techniques are regaining popularity. We will discuss in this review several factors that strongly justify the use of the cutaneous tissues and development of alternative methods for vaccination. That includes (1) our improved knowledge of skin physiology and better understanding of the barrier role of the horny layer, (2) the rationalization for targeting the different cutaneous layers, i.e. the epidermis, dermis, or hypodermis, (3) our advances in knowledge of the skin immune system, especially the plasticity of antigen-presenting cells (APCs) (i.e Langerhans cells (LC), dermal dendritic cells (DDC) and dermal macrophages) in the induction of immune responses, (4) the reduction of antigenic dose for some modes of cutaneous administration, (5) the increased need in needlefree vaccination strategies for developing countries to cope with blood contamination issues. Progress in skin immunization methods and better understanding of skin immunity allow proposing innovative and efficient vaccination strategies against infectious diseases.