Central venous catheters (CVCs) are frequently used as vascular access for patients who require hemodialysis, but infectious complications remain a major clinical problem. Specifically, catheter-related bloodstream infections (CRBSIs) have an adverse effect on survival, hospitalization, mortality, and the overall cost of care in this setting. The growing number of patients who require hemodialysis, combined with an increasing number of patients who cannot use any vascular access other than a CVC, stress the importance of strategies to prevent CRBSI. Various interventions aimed at reducing the incidence of CRBSI are available, but they have not yet been integrated into evidence-based, consensus guidelines. In this Review, the results from several CVC infection prevention studies—of patients from dialysis and nondialysis settings—are combined to outline a rational approach to CRBSI prevention. Prevention of intraluminal contamination of the CVC is pivotal and of proven efficacy, as are strict aseptic CVC insertion and handling protocols, use of chlorhexidine in alcohol solutions for skin cleansing, topical application of antimicrobial ointments, and antimicrobial lock solutions. Adherence to a meticulous catheter care protocol can achieve a CRBSI incidence well below one episode per 1,000 catheter days, even without the need for antimicrobial ointments or lock solutions.