Staphylococcus aureus is capable of becoming resistant to all classes of antibiotics clinically available and resistance can develop through de novo mutations in chromosomal genes or through acquisition of horizontally transferred resistance determinants. This review covers the most important antibiotics available for treatment of S. aureus infections and a special emphasis is dedicated to the current knowledge of the wide variety of resistance mechanisms that S. aureus employ to withstand antibiotics. Since resistance development has been inevitable for all currently available antibiotics, new therapies are continuously under development. Besides development of new small molecules affecting cell viability, alternative approaches including anti-virulence and bacteriophage therapeutics are being investigated and may become important tools to combat staphylococcal infections in the future.