Staphylococci are the most abundant skin-colonizing bacteria and the most important causes of nosocomial infections and community-associated skin infections. Molecular determinants of staphylococcal skin colonization include surface polymers and proteins that promote adhesion and aggregation, and a wide variety of mechanisms to evade acquired and innate host defenses. Antimicrobial peptides (AMPs) likely play a central role in providing immunity to bacterial colonization on human epithelia. Recent research has shown that staphylococci have a broad arsenal to combat AMP activity, and can regulate expression of AMP-resistance mechanisms depending on the presence of AMPs. While direct in vivo evidence is still lacking, this suggests that the interplay between AMPs and AMP resistance mechanisms during evolution had a crucial role in rendering staphylococci efficient colonizers of human skin.