Central Line Associated Bloodstream Infections (CLABSIs) have come to be recognized as preventable adverse events that result from lapses in technique at multiple levels of care. CLABSIs are associated with increased mortality and adverse outcomes that may have lifelong consequences. This review provides a summary of evidence-based strategies to reduce CLABSI in the newborn intensive care unit that have been described in the literature over the past decades. Implementation of these strategies in “bundles” is also discussed, citing examples of successful quality improvement collaboratives. The methods of implementation require an understanding of the scientific data and technical developments, as well as knowledge of how to influence change within the unique and complicated milieu of the newborn intensive care unit.