Substance dependence is a prevalent and urgent public health problem. In 2021, 60 million Americans reported abusing alcohol within the month prior to being surveyed, and nearly 20 million Americans reported using illegal drugs (e.g., heroin) or prescription drugs (e.g., opioids) for nonmedical reasons in the year before. Drug-involved overdose rates have been steadily increasing over the past 20 years. This increase has been primarily driven by opioid and stimulant use. Despite its prevalence, drug dependence is one of the most stigmatized health conditions. Stigma has myriad negative consequences for its targets, including limiting their access to employment and housing, disrupting interpersonal relationships, harming physical and mental health, and reducing help-seeking. However, because research on stigma toward people with substance use disorders (SUDs) is relatively sparse compared with research on stigma toward other mental illnesses, the field lacks a comprehensive understanding of the causes and consequences of SUD stigma. Moreover, it remains unclear how, if at all, these factors differ from other types of mental illness stigma. The goal of this review is to take stock of the literature on SUD stigma, providing a clear set of foundational principles and a blueprint for future research and translational activity.