Gram-positive cocci are the most common cause of bloodstream infections in hemodialysis patients, with Staphylococcus aureus and coagulase-negative staphylococci causing most infections. Management of these infections often is complicated by limited vascular access options, as well as an increasing prevalence of drug-resistant bacteria in hemodialysis centers, including the emergence of strains of methicillin-resistant S aureus with vancomycin heteroresistance and increasing rates of vancomycin-resistant enterococci, both of which have limited antibiotic treatment options. This article describes the management of these infections based on the organism and its susceptibility profile, including catheter management, antibiotic lock therapies, and systemic antibiotic choices. Although coagulase-negative staphylococci bacteremia often may be managed with preservation of the catheter, antibiotic lock therapy, and intravenous antibiotics, this is rarely the case with S aureus bacteremia because of frequent relapse and the risk of complications, including endocarditis. Enterococcal bacteremia requires more individualization of care, but catheters are less likely to be salvaged, especially when vancomycin-resistant Enterococcus is the causative organism. Finally, strong infection control policies in the hemodialysis unit, conversion from catheter to arteriovenous access when possible, and appropriate use of antibiotics are essential factors in the prevention of these bloodstream infections.