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Physician-scientists are needed to continue the great pace of recent biomedical research and translate scientific findings to clinical applications. MD–PhD programs represent one approach to train physician–scientists. MD–PhD training started in the 1950s and expanded greatly with the Medical Scientist Training Program (MSTP), launched in 1964 by the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health. MD–PhD training has been influenced by substantial changes in medical education, science, and clinical fields since its inception. In 2014, NIGMS held a 50th Anniversary MSTP Symposium highlighting the program and assessing its outcomes. In 2016, there were over 90 active MD–PhD programs in the United States, of which 45 were MSTP supported, with a total of 988 trainee slots. Over 10,000 students have received MSTP support since 1964. The authors present data for the demographic characteristics and outcomes for 9,683 MSTP trainees from 1975–2014. The integration of MD and PhD training has allowed trainees to develop a rigorous foundation in research in concert with clinical training. MSTP graduates have had relative success in obtaining research grants and have become prominent leaders in many biomedical research fields. Many challenges remain, however, including the need to maintain rigorous scientific components in evolving medical curricula, to enhance research-oriented residency and fellowship opportunities in a widening scope of fields targeted by MSTP graduates, to achieve greater racial diversity and gender balance in the physician–scientist workforce, and to sustain subsequent research activities of physician–scientists.