Human α defensins are disulfide-stabilized antimicrobial peptides produced primarily in neutrophils and Paneth cells of the small intestine. These molecules are essential not only in innate immunity through killing invading bacteria, fungi, and viruses, but also in adaptive immunity by modulating immune responses. Recent advances in peptide chemistry have enabled us to study multiple signature structural elements in these molecules, including three disulfide bonds, a salt bridge, a conserved glycine residue in a beta bulge, multiple arginine residues, and a C-terminal aromatic residue. In addition to these elements of the mature domain, the N-terminal propetide is involved in interacting with and modulating the function of the mature domain. Gaining insight into functional implications of these structural elements improves our understanding of how human alpha defensins work at the molecular level in innate and adaptive immunity.