Catheter-related bloodstream infection and catheter occlusion are potential significant complications of parenteral nutrition therapy. The increased incidence and associated morbidity, mortality, increased costs, and quality-of-life issues experienced with these adverse events necessitate specialized management of vascular access devices. The host coagulation response to biomaterials and the associated development of biofilm on vascular devices are complex phenomena. Multiple interventions are required to prevent access of bacteria to both intraluminal and extraluminal catheter surfaces, and the occurrence of catheter occlusion. The discovery of the biofilm form of microbial life and the associated recalcitrance of biofilm bacteria to antimicrobials has provided insight into the failure of current prevention, diagnostic, and treatment protocols. Critical interventions are presented correlating current evidence with new discoveries in pathogenesis.