Hospital-acquired infections are a leading cause of morbidity and mortality in neonatal intensive care units. Central line–associated blood stream infection (CLABSI) and ventilator-associated pneumonia (VAP) are costly, preventable infections targeted for eradication by the Centers for Disease Control and Prevention. After evaluation of current practice and areas for improvement, neonatal-specific CLABSI and VAP bundles were developed and implemented on the basis of available best evidence. The overall goal was to reduce infection rates at or below benchmarks set by National Healthcare Safety Network. All neonates with central lines (umbilical or percutaneous) and/or patients who were endotracheally intubated were included. All patients were risk stratified on the basis of weight per National Healthcare Safety Network reporting requirements: less than 750 g, 751–1000 g, 1001–1500 g, 1501–2500 g, and greater than 2500 g. The research was conducted as a quality improvement study. Neonatal-specific educational modules were developed by neonatal nurse leaders for CLABSI and VAP. Bundle development entailed combining select interventions, mainly from the adult literature, that the nurse leaders believed would reduce infection rates. Nursing practice guidelines and supply carts were updated to ensure understanding, compliance, and convenience. A CLABSI checklist was initiated and used at the time of line insertion by the nurse to ensure standardized infection control practices. Compliance audits were performed by nurse leaders weekly on intubated patients to validate VAP bundle implementation. CLABSI and VAP bundle compliance was audited and infection rates were measured before and after both bundle implementations following strict National Healthcare Safety Network inclusion criteria for CLABSI and VAP determination. The reduction in CLABSI elicited 84 fewer hospital days, estimated cost savings of $348,000, a 92% reduction in CLABSI (preintervention to postintervention), and a reduction in central line days by 27%. The reduction in VAP resulted in 72 fewer hospital days, estimated cost savings of $300,000, 71% reduction in VAP (preintervention to postintervention), and a reduction in vent days by 31%. Nurses are central in hospital efforts to improve quality care. The bundled interventions provided the nurses with a structure to successfully implement a systematic process for improvement. Nursing leaders ensured that bundles were implemented strategically and provided consistent and specific feedback on intervention compliance with quarterly CLABSI and VAP rates. Real-time feedback assisted the registered nurses, neonatal nurse practitioners, and physicians appreciation of the effectiveness of the change in practice. Finally, empowering the bedside nurse to lead the bundle implementation increased personal ownership and compliance and ultimately improved practice and patient outcomes.