Staphylococcus aureusis one of the most common opportunistic human pathogens causing several infectious diseases. Ever since the emergence of the first methicillin-resistantStaphylococcus aureus(MRSA) strain decades back, the organism has been a major cause of hospital-acquired infections (HA-MRSA). The spread of this pathogen across the community led to the emergence of a more virulent subtype of the strain, i.e., Community acquired Methicillin resistantStaphylococcus aureus(CA-MRSA). Hence, WHO has declaredStaphylococcus aureusas a high-priority pathogen. MRSA pathogenesis is remarkable because of the ability of this “superbug” to form robust biofilm bothin vivoandin vitroby the formation of polysaccharide intercellular adhesin (PIA), extracellular DNA (eDNA), wall teichoic acids (WTAs), and capsule (CP), which are major components that impart stability to a biofilm. On the other hand, secretion of a diverse array of virulence factors such as hemolysins, leukotoxins, enterotoxins, and Protein A regulated byagrandsaetwo-component systems (TCS) aids in combating host immune response. The up- and downregulation of adhesion genes involved in biofilm formation and genes responsible for synthesizing virulence factors during different stages of infection act as a genetic regulatory see-saw in the pathogenesis of MRSA. This review provides insight into the evolution and pathogenesis of MRSA infections with a focus on genetic regulation of biofilm formation and virulence factors secretion.