The comorbidity of substance use disorders (SUDs) with anxiety and depression is the focus of substantial research attention and approached from myriad perspectives. This chapter focuses on the resultant complex research literature, first providing an overview of epidemiologic studies that have examined the prevalence of co-occurrence of SUDs (including alcohol and other drug use disorders) with anxiety and depressive disorders, as well as clinical correlates of these forms of comorbidity. Next, theoretical models of the onset and maintenance of emotional disorder–SUD comorbidity are considered, followed by a review of various types of studies evaluating these theoretical models (studies focusing on order-of-onset, the independent versus substance-induced disorder distinction, self-reported motives for use, genetic epidemiology, and experimental studies). Distinctions and commonalities between anxiety–SUD associations and depression–SUD associations are examined throughout. The chapter concludes by examining treatment implications of this comorbidity and suggests future directions for this burgeoning field.