Introduction:Midcareer research faculty are a vital part of the advancement of science in U.S. medical schools, but there are troubling trends in recruitment, retention, and burnout rates.Methods:The primary sampling frame for this online survey was recipients of a single R01 or equivalent and/or K-award from 2013 to 2019. Inclusion criteria were 3–14 years at a U.S. medical school and rank of associate professor or two or more years as assistant professor. Forty physician investigators and Ph.D. scientists volunteered for a faculty development program, and 106 were propensity-matched controls. Survey items covered self-efficacy in career, research, work-life; vitality/burnout; relationships, inclusion, trust; diversity; and intention to leave academic medicine.Results:The majority (52%) reported receiving poor mentoring; 40% experienced high burnout and 41% low vitality, which, in turn, predicted leaving intention (P< 0.0005). Women were more likely to report high burnout (P= 0.01) and low self-efficacy managing work and personal life (P= 0.01) and to be seriously considering leaving academic medicine than men (P= 0.003). Mentoring quality (P< 0.0005) and poor relationships, inclusion, and trust (P< 0.0005) predicted leaving intention. Non-underrepresented men were very likely to report low identity self-awareness (65%) and valuing differences (24%) versus underrepresented men (25% and 0%;P< 0.0005). Ph.D.s had lower career advancement self-efficacy than M.D.s (P< .0005).Conclusions:Midcareer Ph.D. and physician investigators faced significant career challenges. Experiences diverged by underrepresentation, gender, and degree. Poor quality mentoring was an issue for most. Effective mentoring could address the concerns of this vital component of the biomedical workforce.