In this article, we review research on the nature and treatment of panic disorder, and apply these findings to a discussion of the role of internal cue exposure in the treatment of substance use disorders (SUDs). Two features of panic treatment were used as a model for interventions for SUDs: exposure to internal (interoceptive) cues rather than reliance on external (environmental) exposure alone, and use of cue exposure to try to inoculate individuals against future maladaptive patterns. Specifically, we emphasized the role of exposure to internal, largely emotional cues, as a way to enhance resilience to cues for relapse in individuals with SUDs. Hypothesized moderators and mediators of this treatment approach were discussed, as were similarities between this research agenda and an increasing focus on the role of emotional acceptance/tolerance in cognitive-behavioral treatments.