The genus Staphylococcuscomprises more than 40 validly described species, with the coagulase-positive species Staphylococcus aureusand the coagulase-negative species S. epidermidisand S. haemolyticusas the most common causes of healthcare-associated infections caused by staphylococci. Many staphylococcal species are both commensal microorganisms and pathogens. In particular, S. aureusis still one of the most feared pathogens, becoming increasingly virulent and resistant to antibiotic agents. This versatile pathogen harbors a wide array of virulence factors to enable colonization, invasion, aggression, and persistence processes. The study of slow-growing variant forms of S. aureus(i.e., the small-colony variants) has helped in the understanding of the persistent and recurrent infections. In the last decades, methicillin-resistant S. aureusstrains have become endemic in hospitals worldwide, rendering almost all β-lactam antibiotics (penicillins, cephalosporins, and carbapenems) ineffective. Additionally, community-associated methicillin-resistant S. aureusin persons without previous healthcare exposures as well as livestock-associated methicillin-resistant S. aureushave been increasingly reported. The majority of community-associated methicillin-resistant S. aureusstrains have acquired Panton-Valentine leukocidin encoding genes, thereby greatly increasing their virulence. All these new strains and variants represent challenges for clinical microbiologists, infection preventionists, and epidemiologists.