Healthcare-associated infections (HAIs) and community-acquired sepsis can result in significant patient harm. This article describes one large academic hospital’s experience implementing a hospital-wide initiate to reduce HAIs and improve sepsis care.  Key components of the initiative included an awareness campaign and clinician engagement, implementation of HAI and sepsis bundles, electronic health record-based clinical decision support, and education and training. Over a five-year period, the initiative lowered HAI rates, reduced sepsis mortality, and improved safety culture.