Hemodialysis catheter-related bloodstream infections are potentially devastating, leading to increased morbidity, mortality, and cost of care. Prospective studies published over the past 15 years shed light on the pathogenesis of these infections. The data suggest that the intraluminal microbial colonization of hemodialysis catheters often precedes bloodstream infection. This finding supports strategies aimed at preventing or eradicating intraluminal colonization.