Cathelicidins form one of the major families of antimicrobial peptides and have been identified in many vertebrates, including humans. LL-37, the only human member of the cathelicidin family, is detected in most sites of the human body that is normally exposed to microbes, including the epithelial lining of the skin, gastrointestinal tract, genitourinary tract and lungs. This peptide is also expressed by a variety of epithelial cells and immune cells, such as neutrophils, monocytes and mast cells. LL-37 has emerged as a key component of innate immunity due to its direct antimicrobial activity against a broad spectrum of invading pathogens. It also exhibits diverse immunomodulatory functions by activating both pro- and anti-inflammatory mediators; inducing cell migration, proliferation and differentiation; and regulating apoptosis of epithelial cells and neutrophils. Given that the phenotypic and functional properties of immune compartments are different and significantly impacted by the anatomical sites, tissue-specific factors of host origin and microbial communities play important roles in the regulation of LL-37. This review summarizes the expression and biological functions of LL-37 and discusses its significant roles in the innate immune system based on its anatomical distribution.