In recent years, the concept of commercial determinants of health (CDoH) has attracted scholarly, public policy, and activist interest. To date, however, this new attention has failed to yield a clear and consistent definition, well-defined metrics for quantifying its impact, or coherent directions for research and intervention. By tracing the origins of this concept over 2 centuries of interactions between market forces and public health action and research, we propose an expanded framework and definition of CDoH. This conceptualization enables public health professionals and researchers to more fully realize the potential of the CDoH concept to yield insights that can be used to improve global and national health and reduce the stark health inequities within and between nations. It also widens the utility of CDoH from its main current use to study noncommunicable diseases to other health conditions such as infectious diseases, mental health conditions, injuries, and exposure to environmental threats. We suggest specific actions that public health professionals can take to transform the burgeoning interest in CDoH into meaningful improvements in health. (Am J Public Health. 2021;111(12):2202-2211. https://doi.org/10.2105/AJPH.2021.306491).