Academic medicine is entering an era of profound, unsettling change resulting not simply from the drastic transformation of the health care marketplace but more fundamentally from the chronic, growing gap between academic medicine's seemingly insatiable demand for total resources and the supply of resources that society is willing to provide. To examine this problem, the author reviews the major factors that have shaped the development of academic medical centers (AMCs) since World War II and are now the roots of their vulnerability. The first was the major federal investment in university-based programs of science research and education that began in the 1940s; the second was the enactment in the 1960s of the Medicare/Medicaid legislation that established federal responsibility for the support of graduate medical education. After describing important characteristics (e.g., number of faculty, number of students, dollars spent on research) of the growth and accomplishment that resulted from this massive infusion of federal funds over the last few decades, the author discusses several adverse consequences, such as the de-emphasis on education in favor of research and clinical service delivery and the serious disjunction between the internal labor markets of the AMCs and the external labor markets of the real world that AMCs' graduates enter. The author then analyzes the severe challenges being faced by academic medicine in research, education, and clinical practice in the emerging resource-limited environment. Of particular concern are the fate of the clinical investigator and the future of clinical research. The author concludes with a list of four feasible strategic options for AMCs (e.g., "build one's own system") and an extensive list of what he believes AMCs will do to respond to the stresses now upon them (e.g., capitalize on unique strengths rather than trying to compete in all areas). He concludes that it will take courage for AMCs to preserve their core values in the new era, but that this can be done if AMCs craft new adaptive structures that are better attuned to the new environment and not wedded to one that is vanishing.