Analysis of staphylococcal resistance to antimicrobial agents has revealed three main biochemical mechanisms of resistance that are common to other bacteria: (1) inactivation of the antimicrobial by enzymes modifying or hydrolysing the agent, (2) target receptor alteration – by acquisition of a target with reduced affinity for the antimicrobial, acquisition of enzymes converting a native target, or mutation of genes encoding the native target, (3) limiting access of the antimicrobial, mainly by active efflux of the antibiotic. Often, several mechanisms confer resistance to the same antimicrobial agent. Staphylococcal resistance has evolved by acquisition of resistance determinants and by mutation or recombination events in existing staphylococcal DNA. Effective horizontal distribution of DNA among staphylococci is possible via transformation, transduction, plasmid-mediated conjugation or phage-mediated conjugation. Plasmid-mediated DNA mobilization and the location of R determinants on transposable elements are important genetic features of Staphylococcus, allowing versatility of resistance.