BACKGROUND: The co-occurrence of depression and substance use disorders (SUD) is highly prevalent and associated with poor treatment outcomes for both disorders. As compared to individuals suffering from either disorder alone, individuals with both conditions are likely to endure a more severe and chronic clinical course with worse treatment outcomes. Thus, current practice guidelines recommend treating these co-occurring disorders simultaneously. OBJECTIVES: The overarching aims of this narrative are two-fold: (1) to provide an updated review of the current empirical status of integrated psychotherapy approaches for SUD and depression comorbidity, based on models of traditional cognitive-behavioral therapy (CBT) and newer third-wave CBT approaches, including acceptance- and mindfulness-based interventions and behavioral activation (BA); and (2) to propose a novel theoretical framework for transdiagnostic CBT for SUD-depression, based upon empirically grounded psychological mechanisms underlying this highly prevalent comorbidity. RESULTS: Traditional CBT approaches for the treatment of SUD-depression are well-studied. Despite advances in the development and evaluation of various third-wave psychotherapies, more work needs to be done to evaluate the efficacy of such approaches for SUD-depression. CONCLUSION: Informed by this summary of the evidence, we propose a transdiagnostic therapy approach that aims to integrate treatment elements found in empirically supported CBT-based interventions for SUD and depression. By targeting shared cognitive-affective processes underlying SUD-depression, transdiagnostic treatment models have the potential to offer a novel clinical approach to treating this difficult-to-treat comorbidity and relevant, co-occurring psychiatric disturbances, such as posttraumatic stress.