Despite the growing disparity between organ supply and demand in the United States, few initiatives have attempted to close the gap through systematic population-based public health endeavors. We examined the evolution, implementation, and outcomes of the Massachusetts Organ Donation Initiative, a statewide effort that included a unique partnership among organ procurement organizations, major teaching hospitals, and the state's department of public health. Lessons from this initiative have contributed to growing national efforts for increasing organ supply and have provided insights for addressing this continuing public health challenge.