Substances of abuse are characterized by their rewarding effects and engagement of reward pathways in the brain. However, these substances also provide rapid relief of negative affect, and thus are highly negatively reinforcing. Accordingly, negative affectivity and other affective vulnerabilities (factors related to the experience of affect) are strongly linked to problematic substance use and substance use disorders. In this review, we provide a critical overview of the literature on affective vulnerabilities in substance use disorders. We discuss how both the experience of affect (e.g. negative affectivity, stress reactivity) and the interpretation of affect (e.g. distress intolerance, anxiety sensitivity) are pertinent to the development, maintenance, and treatment of substance use disorders.