Antimicrobial peptides are diverse and evolutionarily ancient molecules produced by all living organisms. Peptides belonging to the cathelicidin and defensin gene families exhibit an immune strategy as they defend against infection by inhibiting microbial survival, and modify hosts through triggering tissue-specific defense and repair events. A variety of processes have evolved in microbes to evade the action of antimicrobial peptides, including the ability to degrade or inactivate antimicrobial peptides, or suppress host production of the peptide in response to infection. Animal models and clinical investigations have shown that an absence of cathelicidin or defensin antimicrobials can lead to disease. In this article, we review important recent advances in understanding the biology of antimicrobial peptides and their role in normal immunity and human disease.