The human skin represents the first line of defense against potentially hazardous environmental threats (ie, infection by microbes, such as viruses, bacteria, and fungi). To fulfill this crucial function and to maintain the integrity of the skin compartment, evolution has equipped the human immune system with a variety of sophisticated tools leading to an efficient defense system of responses to various infectious challenges. The role of the skin within the different defense lines is multifaceted. The central role of the immune defense system is performed by the group of "pathogen-associated pattern recognition receptors," among which the group of Toll-like receptors (TLRs) has evolved as the central family during the last years. Ten TLRs are identified in humans, all of which share similarities in their structure and function, but respond to different microbial components.