Improving quality and safety across an entire healthcare system in multiple clinical areas within a short time frame is challenging. We describe our experience with improving inpatient quality and safety at Kaiser Permanente Northern California. The foundations of performance improvement are a “four-wheel drive” approach and a comprehensive driver diagram linking improvement goals to focal areas. By the end of 2011, substantial improvements occurred in hospital-acquired infections (central-line–associated bloodstream infections and Clostridium difficile infections); falls; hospital-acquired pressure ulcers; high-alert medication and surgical safety; sepsis care; critical care; and The Joint Commission core measures.