Defensins are a family of antimicrobial cationic peptides that act as a rapid response force against microbial invasion in a wide range of organisms, including plants, insects, animals and humans. In humans, defensins are produced predominantly by leukocytes and epithelial cells and are an important factor of innate immunity. In addition to their major role as natural antibiotics, defensins are increasingly recognized as signaling molecules in adaptive immunity and aberrant defensin expression has been associated with infectious diseases. In this review, we discuss the role of human defensins in relation to infectious disease and the possibility of novel defensin-based therapeutic approaches.