Phagocytic leukocytes are a central cellular element of innate-immune defense in mammals. Over the past few decades, substantial progress has been made in defining the means by which phagocytes kill and dispose of microbes. In addition to the generation of toxic oxygen radicals and nitric oxide, leukocytes deploy a broad array of antimicrobial proteins and peptides (APP). The majority of APP includes cationic, granule-associated (poly)peptides with affinity for components of the negatively charged microbial cell wall. Over the past few years, the range of cells expressing APP and the potential roles of these agents have further expanded. Recent advances include the discovery of two novel families of mammalian APP (peptidoglycan recognition proteins and neutrophil gelatinase-associated lipocalin), that the oxygen-dependent and oxygen-independent systems are inextricably linked, that APP can be deployed in the context of novel subcellular organelles, and APP and the Toll-like receptor system interact. From a clinical perspective, congeners of several of the APP have been developed as potential therapeutic agents and have entered clinical trials with some evidence of benefit.