The epidemiology of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has evolved over the past approximately 20 years, with certain populations appearing to have disproportionate risk. Of concern is the potential worsening of S. aureus infections in light of the continued opioid crisis. This review will discuss how CA-MRSA has significantly impacted HIV-infected individuals and address additional factors and populations that are associated with increased risk for MRSA. It will review therapeutic options and infection control strategies as well as highlight how whole genome sequencing can be used to extend traditional epidemiologic analysis and ultimately, inform infection prevention efforts. Continued work identifying those at the highest risk for MRSA, what the best infection prevention settings are in community settings and how to effectively implement and target these strategies is needed. Ultimately, infection control efforts will likely need to extend beyond healthcare settings to effectively and sustainably reduce MRSA infections.