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Antimicrobial peptides are effectors of innate immunity in phagocytes, body fluids and epithelia. In mammals, defensins, peptides with a characteristic six-cysteine framework, are particularly abundant and widely distributed in various animal species and tissues. The first part of this review provides a historical overview of the ideas that led to the current state-of-the-art in antimicrobial peptides, and the second part is an update on mammalian defensins and their role in host defense to infections.