Strategies that foster a positive safety culture are increasingly supported by emerging relationships between hospital safety culture and adverse events, such as readmissions. Teamwork training, executive walk rounds, and establishing unit-based safety teams are all initiatives associated with improvements in safety culture measurement. This study describes a hospital-wide initiative that significantly improved nearly all safety culture domains in 144 clinical units over a 3-year period. The initiatives implemented included a comprehensive unit-based safety program (CUSP), specific teamwork and communication tools, a series of educational venues, and investments in infrastructure and leadership positions. A past AHRQ WebM&M conversation and perspective discussed important facets of safety culture in health care.