Staphylococcus aureus continues to be a serious health problem worldwide due to its intrinsic nature of virulence, ability to cause a wide array of infection, and its capacity to develop resistance to a number of antibiotics. The S aureus genome has continually evolved through both mutation and acquisition of exogenous genes, leading to the emergence of antibiotic-resistant strains with the ability for clonal dissemination across nations and continents. Methicillin-resistant S aureus (MRSA) is one of the most commonly identified antibiotic-resistant pathogens in the hospital and community settings with substantial mortality and morbidity. This review examines the accessory genome of 8 sequenced S aureus strains regarding the variety of virulence factors and mechanisms of antibiotic resistance. The remarkable nature of this organism to acquire and disseminate an array of mobile genetic elements (MBEs) through horizontal gene transfer illustrates the mechanisms for evolution and its fitness level in the face of constant environmental challenges. The relative ease of transfer of genetic materials, especially antibiotic-resistant genes, across staphylococcal species indicates that there is a potential pandemic problem in the hospital and community environment.