Bacterial pathogens colonize human body surfaces soon after birth. In order to survive the constant threat of invasion and infection, the human innate immune system has evolved several efficient mechanisms to prevent harmful microorganisms from traversing epithelial barriers. These include cationic antimicrobial peptides (CAMPs) such as defensins and the cathelicidin LL-37, bacteriolytic enzymes such as lysozyme, antimicrobial fatty acids, toxic oxygen- or nitrogen-containing molecules, the bacteriolytic complement components and further mechanisms with indirect impacts on bacterial multiplication. Staphylococcus aureus is an important human commensal and pathogen. In order to successfully establish an infection, S. aureus has evolved several mechanisms to resist the innate immune system. In this review, we focus on the mechanisms employed by S. aureus to achieve protection against antimicrobial host defense molecules with special emphasis on CAMPs. Lessons from recent studies on antimicrobial host defense molecules and cognate bacterial resistance adaptation should help in the development of more sustainable anti-infective compounds.