Staphylococcus aureus, a unique and potentially lethal organism, can cause bacteremia resulting in metastatic complications. S. aureus has characteristics that distinguish it from other bloodstream pathogens. These include membrane-bound attachment proteins enabling the bacteria to infect tissues in all parts of the body. Risk factors for developing complicated S. aureus bacteremia (SAB) include acquiring the infection in a community setting, a history of previous endocarditis, recent intravenous procedures such as dialysis, heart structure/valve abnormalities, and the presence of intravascular and prosthetic hardware. Physical examination findings may include any tissue of the body (eg, Roth spots in the eye, embolic manifestations, psoas abscess, and vertebral osteomyelitis). Differentiating between complicated and uncomplicated SAB is a key objective. Predictors of complicated SAB include a positive follow-up blood culture at 48 to 96 hours, community onset, persistent fever at 72 hours, skin lesions, and an abnormal transesophageal echocardiogram. All patients with SAB should be treated for at least 4 weeks. Only in well-defined cases, under the care of an infectious disease specialist, should patients with SAB be treated for a shorter period.