The National Institutes of Health (NIH) is the most prominent funding source for scientific research in the world. It is also a complex and diverse organization, having multiple institutes, centers and offices. NIH emphasizes the need for innovation and collaboration in research to discover critical knowledge, enhance health and prevent disease. Advancement in science requires not only sophisticated methods, but also logical organization. Here, an overview of ‘behavioral research’ (writ large) at NIH is presented, focusing upon the common trinity of ‘alcohol, tobacco/nicotine and other drugs’ and programmatic overlap across entities. Consideration is also given to the origins of institutes and their historical movement across organizational boundaries. Specific issues, concerns and advantages of integration of the National Institute on Drug Abuse and National Institute on Alcoholism and Alcohol Abuse are addressed. It is concluded that advances in understanding, treating and preventing substance use disorders would best be served by (1) review and integration of all related research throughout NIH, (2) logical placement of leadership for this activity in a single institute, here entitled the National Institute on Substance Use Disorders, and (3) close collaboration of this institute with its complementary partner, the National Institute on Mental Health. Thus, NIH can establish an organizational structure and collaborations reflecting the realities of the scientific and disease/health domains. This would make a prominent statement to the world scientific and health communities regarding NIH recognition of the need for innovation (scientific and organizational) and focus upon these myriad interrelated and costly problems.