Mistrust of medical advances and the medical professions continues to persist, and is perhaps increasing. The popular press has documented the growing number of parents globally whose concerns around childhood vaccination, albeit based on faulty scientific information, has led to the anti-vax movement which has already resulted in outbreaks of measles in various parts of the U.S. In recent years, the AIDS Healthcare Foundation has increased speculation and mistrust with regard to the denialism of the effectiveness of pre-exposure prophylaxis (PrEP) to avert HIV infections, again based on misinformation. However, in other cases, medical mistrust reflects the very real historical and ongoing injustices experienced by socially and economically marginalized groups. Whether the genesis of the mistrust is based on fact or fallacy, the results may be similar. There are myriad negative consequences associated with medical mistrust, including lower utilization of healthcare and poorer management of health conditions. Mistrust is thought to provide a partial explanation for staggering health disparities, particularly among Black and African American people, and much of the public health and medical literature cites the infamous Tuskegee Study as a main catalyst for this persistent health-related mistrust among people of color and other groups who experience social and economic vulnerability. While mistrust is often referred to as a phenomenon existing within an individual or community, we must rethink this conceptualization and instead locate mistrust as a phenomenon created by and existing within a system that creates, sustains and reinforces racism, classism, homophobia and transphobia, and stigma. The purpose of this article is to briefly address the state of the medical mistrust literature, and to provide a summary of the articles included in this special issue on medical mistrust. Although the scholarship in this issue addresses diverse methodologies, outcomes and populations, they share a message: social inequality drives mistrust.