Eukaryotic antibiotic peptides are key components of innate immunity. They act as a first barrier against invading pathogens. Expectations about their clinical use have been raised as they are active against a wide range of pathogens, and unlikely to induce resistance. Both characteristics are related to their lethal mechanism, based on interaction with anionic phospholipids in the outer facet of the cytoplasmic membrane of the pathogens, leading to permeabilization. This review will especially focus on antibiotic peptides of human origin. Their mechanism of action, strategies of pathogen resistance, and role in activities other than microbicidal effect will be described. Practical applications and prospects of future use in anti-infectious therapy will also be discussed.