The stakes for the prevention of central line associated bloodstream infections (CLABSIs) have increased dramatically over the past decade. Over the past 10 years, the rate of CLABSI in the pediatric population has dropped markedly due to the significant investment in this initiative. Although there has been a substantial increase in studies on CLABSIs, difficulties in studying CLABSIs have limited the quality of the evidence produced. These difficulties include challenges in the sample size required to complete trials, pressure from external regulatory forces to reduce CLABSI rates, and challenges in defining CLABSIs. The definition of CLABSI is continuously being updated to improve the misclassification bias inherent in defining CLABSI. This is especially relevant given the stress placed on decreasing health-care-associated infections and the negative consequences associated if unsuccessful. In order to prevent CLABSIs, pediatric and neonatal intensive care units have formed bundles of basic evidenced-based strategies leading to effective reduction of CLABSIs. These basic bundles have been modified for spread to other nonintensive care areas, also yielding great results. However, additional therapies above the basic bundle have yielded mixed results, and more research is needed to understand the cost effectiveness of these therapies in the setting of decreasing CLABSI rates. As a goal, a "getting to zero" CLABSI rate should be set, but it may not be possible without significant resource allocation.