Staphylococcus aureus is an important human pathogen, responsible for infections in the community and the healthcare setting. Although much of the attention is focused on the methicillin-resistant “variant” MRSA, the methicillin-susceptible counterpart (MSSA) remains a prime species in infections. The epidemiology of S. aureus, especially of MRSA, showed a rapid evolution in the last years. After representing a typical nosocomial multidrug-resistant pathogen, MRSA has recently emerged in the community and among farmed animals thanks to its ability to evolve and adapt to different settings. Global surveillance has shown that MRSA represents a problem in all continents and countries where studies have been carried out, determining an increase in mortality and the need to use last-resource expensive antibiotics. S. aureus can easily acquire resistance to antibiotics and MRSA is characteristically multidrug resistant. Resistance to vancomycin, the principal anti-MRSA antibiotic is rare, although isolates with decreased susceptibility are recovered in many areas. Resistance to the more recently introduced antibiotics, linezolid and daptomycin, has emerged; however, they remain substantially active against the large majority of MSSA and MRSA. Newer antistaphylococcal drugs have been developed, but since their clinical use has been very limited so far, little is known about the emergence of resistance. Molecular typing techniques have allowed to identify the major successful clones and lineages of MSSA and MRSA, including high-risk clones, and to trace their diffusion. In the face of a continuously evolving scenario, this review depicts the most common clones circulating in different geographical areas and in different settings at present. Since the evolution of S. aureus will continue, it is important to maintain the attention on the epidemiology of S. aureus in the future with a global view.