Central line-associated bloodstream infections (CLA-BSI) are one of the leading causes of healthcare-associated infections, resulting in significant morbidity and substantial excess cost. There is a growing recognition that most CLA-BSIs are preventable. Elimination of preventable CLA-BSI is the focus of a recently released CDC Guideline. Universal preventative measures include collaborative performance improvement using checklists and bundles, education of persons who insert and maintain catheters, maximal sterile barrier precautions, and chlorhexidine skin preparation. Technologic innovations including coated catheters, antimicrobial impregnated dressings, and antimicrobial lock solutions should be considered if the rate of CLA-BSI is not acceptable after application of universal precautions.