Staphylococci are abundant bacteria of the human skin microbiome. Several species, particularly Staphylococcus aureus and Staphylococcus epidermidis, are opportunistic pathogens and cause significant disease. The human skin serves many functions and here we review its role as an antimicrobial barrier and the staphylococcal mechanisms to colonize and counteract the various stresses present in this niche. Successful colonization is achieved using a diversity of adhesins, surface proteins and secreted enzymes to counteract the antimicrobial peptides, enzymes and lipid matrix components present in the acid mantle. Further mechanisms enable these bacteria to overcome osmotic and acid stresses and desiccation in order to survive the exacting demands of an ever-changing landscape.