Excessive substance use and substance use disorders (SUDs) are common, serious and relapsing medical conditions. They frequently co-occur with other diseases that are leading contributors to disability worldwide. While heavy substance use may potentiate the course of some of these illnesses, there is accumulating evidence suggesting common genetic architectures. In this narrative review, we focus on four heritable medical conditions – cardiometabolic disease, chronic pain, depression and COVID-19, which are commonly overlapping with, but not necessarily a direct consequence of, SUDs. We find persuasive evidence of underlying genetic liability that predisposes to both SUDs and chronic pain, depression, and COVID-19. For cardiometabolic disease, there is greater support for a potential causal influence of problematic substance use. Our review encourages de-stigmatization of SUDs and the assessment of substance use in clinical settings. We assert that identifying shared pathways of risk has high translational potential, allowing tailoring of treatments for multiple medical conditions. FUNDING: SSR acknowledges T29KT0526, T32IR5226 and DP1DA054394; RLK acknowledges AA028292; AA acknowledges DA054869 & K02DA032573. The funders had no role in the conceptualization or writing of the paper.