The skin not only plays an important role as a physical barrier between the host and the environment, but also plays a key immunologic role in sensing and responding to invading pathogens from the environment. Toll-like receptors (TLRs), which are expressed by many different types of cells in human skin, have been found to be important pattern recognition receptors that are involved in recognizing components of microbial pathogens and initiating and instructing cutaneous immune responses. This review examines the similarities and differences among the ten known TLRs in humans. In addition, the role of TLRs in cutaneous host defense mechanisms against a variety of microorganisms, including bacteria, fungi, and viruses, as well as the involvement of TLRs in the pathogenesis of certain skin diseases will be discussed.