More than 18 million Americans currently have diabetes mellitus. The economic and human cost of the disease is devastating. In the United States, diabetes is the most common cause of blindness among working-age adults, the most common cause of nontraumatic amputations and end-stage renal disease, and the sixth most common cause of death. For the cohort of Americans born in 2000, the estimated lifetime risk for diabetes is more than 1 in 3. In the next 50 years, the number of diagnosed cases of diabetes is predicted to increase by 165% in the United States, with the largest relative increases seen among African Americans, American Indians, Alaska Natives, Asian and Pacific Islanders, and Hispanic/Latino persons. Compelling scientific evidence indicates that lifestyle change prevents or delays the occurrence of type 2 diabetes in high-risk groups. This body of evidence from randomized, controlled trials conducted in 3 countries has definitively established that maintenance of modest weight loss through diet and physical activity reduces the incidence of type 2 diabetes in high-risk persons by about 40% to 60% over 3 to 4 years. The number of persons at high risk for type 2 diabetes is similar to the number of persons who have diabetes. This paper summarizes scientific evidence supporting lifestyle intervention to prevent type 2 diabetes and discusses major policy challenges to broad implementation of lifestyle intervention in the health system.