**1. Introduction**

Multi-Drug Resistance *of S. aureus* is a massive concern in the clinical world. Immunocompromised, diabetic, and weak immune systems are general medical problems but patients already suffering from these are more susceptible to the Staphylococcal infections and mainly by *S. aureus* which causes skin infections and soft tissue infections. The severity of the infections caused by *S. aureus* increases when there is overgrowth of the *S. aureus* on the infected part of the body which results in the secretion of toxins and causes a fatal condition known as toxic shock syndrome. Penicillin was used predominantly against infections caused by *S. aureus* but the organism started having resistant strains developed for fighting against Penicillin. Methicillin was the next approach that came up for *S. aureus* but the major failure of methicillin by forming MRSA strains made vancomycin the last hope for *S. aureus* infections. Methicillin is the synthetic antibacterial drug given to *S. aureus* widely. *S. aureus* is resistant to almost all antibiotic drugs that are so far used and among them Methicillin and Vancomycin are the two drugs that have shown resistance in *S. aureus*. In this, we will emphasize the genetic aspects of the resistance that is observed in *S. aureus*. The antibiotic resistance genes are generally present on plasmids, and nonessential for the survival of the organism but it provides the bacterial population with a means to reduce the genetic and physiological load on the majority of cells. Plasmid-borne genes can undergo more radical evolutionary changes without affecting the viability of the cell, as would changes to indispensable chromosomal genes, and established plasmid transfer mechanisms can provide recipient cells with new genetic material which has already been refined by selective pressures elsewhere. Besides plasmids, bacteriophages too have contributed towards development of resistance by transduction. Thus the continuous evolution of *S. aureus* strains was successful to bring forth the vancomycin-resistant strains as well (VRSA). New drug development and treatments are applied to the *S. aureus* mediated infections which have proved to be the immediate possible treatment for this. This chapter will help the readers to acquire a comprehensive knowledge regarding the Multi-Drug Resistance of *S. aureus* along with the resistance mechanism and possible treatments of *Staphylococcal* infections.
