The innate immune system is primarily responsible for prevention of infection of the skin by pathogens, but is also important in control of inflammation. The components of innate immunity are frequently misunderstood based on a historical bias for leukocyte-mediated immune defense. Many participating cell types are often overlooked, in particular epithelial cells that provide an early and critical step to innate immune defense. This review will discuss our epithelial barrier to infection with emphasis on how microbes subvert this system, and human diseases associated with these events.