A cutaneous barrier defends the body against invading pathogenic microorganisms due to both innate and adaptive immunity. The innate immune system comprises hundreds of peptides/proteins, which have potent microbicidal activities at low concentrations. Among these microbicidal agents, an increasing body of research has suggested that a vast arsenal of antimicrobial peptides composed of defensins and cathelicidins are key players in cutaneous immunity. Mainly produced by phagocytes and epithelial cells, defensins and cathelicidins directly or indirectly kill a wide range of bacteria, fungi, and viruses. However, it is increasingly evident that these peptides not only act as endogenous antibiotics but also display additional roles, such as regulation of inflammatory and immune responses, chemoattracting immune or inflammatory cells to wound or infection/inflammation sites, acceleration of angiogenesis, promotion of wound healing, and reepithelization, and binding and neutralizing of lipopolysaccharides. Here, we review the skin-derived antimicrobial peptides with an emphasis on their role in skin immune responses. We present an overview of defensin and cathelicidin structure and expression, clarify their various functions beyond microbicidal properties, and describe their modes of action. Moreover, we discuss the roles of these peptides in skin diseases and highlight their possible use in near therapeutic development.