Support of the U.S. health professions investigator workforce is critically important to the continued advancement of health care nationally. Physician-investigators comprise one segment of this health professions investigator workforce, which also includes investigators in the nursing, pharmacy, and dentistry professions, and others. Among physician health professionals in particular, the term "physician-investigator" has been described as encompassing physicians engaged in research in various ways including "clinical researchers" (physicians with clinical duties who do clinical, patient-centered research), "clinician-scientists" (physicians with clinical roles who perform research in laboratories or using computational tools), and "physician-scientists" (physicians focused on research with little or no clinical activity). Broadly defined, physician-investigators are included in various groups of researchers described in several articles recently published in Academic Medicine; these articles provide details on a range of approaches, with supporting outcomes data, being taken to train, support, and retain physicians in the health professions investigator workforce. The authors of this commentary examine selected literature, including several articles in this issue among others, along with Association of American Medical Colleges data, to offer observations about programs that train physician-investigators. Evidence-informed single-program approaches for early-career researchers can sustain continued research interest and foster the career development of the emerging physician-investigator workforce. Collaborative multi-institutional approaches offer the benefit of multisite work to power outcomes studies and to increase generalizability beyond a specific institutional program. System-wide institutional approaches may be particularly critical in supporting physician-investigators across all career stages. Although the articles discussed in this commentary are largely (although not exclusively) focused on various initiatives and programs designed to develop and sustain the physician-investigator workforce, such initiatives and programs may have value in addressing shared challenges of developing, supporting, and retaining the broader investigator workforce across all health professions.