Human and other vertebrate leukocytes contain multiple distinct antimicrobial (poly) peptides. Of these, BPI is a LPB protein active against gram-negative bacteria, PLA2 specifically cleaves bacterial phospholipids, while defensins and cathelicidins are broad spectrum antimicrobials that preferentially permeabilize microbial membranes. These and other polypeptides function in both phagocytic and extracellular killing of microbes, attacking multiple molecular targets to cooperatively penetrate and disrupt the microbial surfaces and membrane barriers. Such antimicrobial substances are of interest not only for students of phagocytic and epithelial host defenses but may lead to the development of novel pharmaceuticals for the treatment of infections and their sequellae.