In this article aimed at hospitalists, we examine the literature on preventive measures for central line-associated bloodstream infections (CLABSIs) and optimal management once a CLABSI has been established. We focus on a number of core preventive measures and the contemporary approach of bundling these measures for maximal impact in reducing infection rates. We then discuss empiric and pathogen-specific antibiotic therapy, including the role of newer antimicrobial agents, as well as the management of an infected central venous catheter.