Antimicrobial peptides (AMPs) are expressed in the respiratory tract and act as effector substances of the innate immune system. A variety of cells synthesize and secrete AMPs including epithelial and professional host defense cells such as neutrophils, macrophages, and NK cells. In the human lung, Β-defensins originate from epithelial cells, macrophages and lymphocytes. α-defensins are synthesized by neutrophils. LL-37/hCAP-18 is produced by epithelial cells, neutrophils, lymphocytes, and macrophages. AMPs act as endogenous antibiotics by direct destruction of microorganisms. Recently, it became clear that AMPs bind to cellular receptors and activate a variety of cell types such as airway epithelial cells, endothelial cells, mast cells, macrophages, dendritic cells, and neutophils amongst others. Concentrations of AMPs in lung secretions are altered in several pulmonary diseases. This chapter describes the basic and applied biology of AMPs in the human lung and their potential role in pulmonary disease.