Antimicrobial peptides have long been presumed to act as effector molecules of innate immunity. However, direct evidence that antimicrobial peptides have central roles in host defence has only recently become available. An overview of the types and characteristics of endogenous human antimicrobial peptides and proteins is presented, with particular emphasis on peptides that are active against HIV. These antiviral peptides are discussed in the context of utilising natural peptides for the design of effective topical microbicides for the treatment of sexually transmitted infections (STIs). Several antimicrobial peptides, termed minidefensins, are potently active against HIV, and bear structural similarity to their larger defensin cousins. Strategies to develop potent peptide antibiotics based on defensin and minidefensin templates are promising in the development of antiviral therapeutics and preventatives.