The human skin is constantly exposed to microbial pathogens but infections only rarely occur. Innate cutaneous immunity is a primary system for protection against infection, and antimicrobial peptides (AMPs) expressed in skin are essential defence molecules. The AMPs include molecules such as the defensins that were first characterized for their antimicrobial properties as well as other peptides and proteins first known for their activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins are unique AMPs that act as defensive and signalling molecules. Two different pathways are involved in this function: cathelicidins have direct antimicrobial activity and they also initiate a host of cellular responses in cytokine release, inflammation and angiogenesis. Several skin diseases are associated with cathelicidin dysfunction. In atopic eczema, for example, cathelicidin expression is suppressed, whereas in rosacea cathelicidin peptides are abnormally processed to forms that induce cutaneous inflammation and a vascular response. In psoriasis cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Current studies have unexpectedly identified vitamin D3 as a major factor for the regulation of cathelicidin expression. This finding may provide new strategies in the management of infectious and inflammatory diseases of the skin by targeting control of the expression and function of cathelicidin and other AMPs.