This Research Topic highlights different mechanisms associated with the skin immune response against infectious agents. The skin was originally defined as a tissue that covers the body, protecting internal tissues and organs from external physical, chemical, and biological aggressions. A greater understanding of the particularities of the skin immune response began with the identification of skin-associated lymphoid tissues (SALT) (1, 2), and the description of the dermal perivascular units (PVU) comprising layers of CD4 and CD8 T cells around capillaries in the dermis (3). SALT and PVU represent examples of the skin immune response organization (4, 5). Thereafter, the skin immune system (SIS) was defined based on work delineating the presence and function of immune cells at this site (6–10). The identification of SIS, SALT, and other skin immune compartments, such as the immune system of the hair follicle (11), helped to change the definition of the skin from a tissue to a linear organ. Due to its size and total weight (approximately 2m2 and about 16% of body weight) it is considered one of the largest organs in the human body. In parallel, the idea of compartmentalization of the immune response with this organ has gained strength via the demonstration of decisive events in the control or development of skin diseases and through studies on the in situ immune response, particularly for infectious skin diseases. The understanding of the dynamics of immune response to different pathogens that penetrate and multiply in the skin has markedly increased. However, much is still unknown about events related to the encounter between the pathogen and the local immune responses and thus this area still requires further investigation. This is the central idea behind this Research Topic and papers within this collection have assessed the impact of the interaction of SIS with different pathogens.