Purpose of Review <p>The prevalence of substance use disorder (SUD) has increased substantially around the world. These increases are associated with severe medical and socioeconomic consequences. Moreover, the simultaneous use of opioids and stimulants among patients with SUD has complicated the treatment and outcomes of treatment approaches.</p> Recent Findings <p>Misuse of these two classes of substances occurs in order to overcome sedative effects of opioids, attenuate the stimulatory responses to stimulants, prolong the clinical effects of both classes of substances, and to experience their synergistic psychoactive effects. In this review, we aim to provide a detailed overview of the co-morbid use and misuse of opioids and stimulants as reported in human. Towards that end, we have included results from studies that have identified the influences of co-opioids and stimulants use on behaviors, cognitive processes, and their effects on physiological aspects and treatment strategies. Finally, the review highlighted the potential significance of identifying these issues when planning behavioral and pharmacotherapeutic approaches against substance use disorders.</p> Summary <p>Future studies will need to pay more attention on identifying genetic causes for co-morbidity as well as structural and neuroplastic changes in the brains of patients who use opioids and stimulants.</p>