Johns Hopkins Medicine—an academic medical center and nonprofit integrated health care delivery system—set a goal in 2002 of making its care the safest in the world. The Comprehensive Unit-Based Safety Program, which trains frontline teams to identify and mitigate patient safety hazards, is a key strategy. The model has been spread to hospitals nationwide and was associated with reductions in central line–associated bloodstream infections in intensive care units. Through its safety efforts, Hopkins has achieved improvements in safety practices such as increased hand-washing, in patient outcomes such as fewer pressure ulcers among patients, and in the hospital staff’s perceptions of the organizational safety culture. Safety principles have been spread outside the hospital setting to the system’s home care group. Success factors include setting ambitious goals, empowering frontline staff to make improvements, involving executives and the board in change, and rigorously measuring and holding units accountable for results.