In the early 2000s, increasing prevalence of psycho-stimulant (e.g., crack/cocaine, methamphetamine) use and related harms, including severe adverse health outcomes, was observed among - mostly marginalized - populations of persons using illicit drugs in North America, underscoring an urgent need for interventions options towards improved prevention and treatment. By about 2010, however, the ‘opioid crisis’, featuring unprecedented use and public health burden, had accelerated into full force in North America, largely muting attention to the psycho-stimulant issue until recently. Recent surveillance data on drug use and related mortality/morbidity from the present decade has documented a marked resurgence of psycho-stimulant use and harms especially in at-risk populations, commonly in direct combination with opioids, across North America, resulting in a ‘twin epidemic’ comprised of opioids and psycho-stimulants We briefly review select epidemiological data indicators for these developments from the United States and Canada; in the latter jurisdiction, related evidence has been less prevalent and systematic but corroborating the same trends. Evidently, the (widely ongoing) focus on the ‘opioid epidemic’ as a ‘mono-type’ drug problem has become an anachronism that requires urgent and appropriate correction. We then briefly consider existing, evidence-based options for – prevention and treatment – interventions targeting psycho-stimulant use and harms, which are substantially more limited and/or less efficacious than those available for problematic opioid use, while presenting major gaps and challenges. The observed resurgence of psycho-stimulants may, indirectly, relate to recent efforts towards curtailing (medical) opioid availability, thereby accelerating demand and supply for both illicit opioids and psycho-stimulants. The presently unfolding ‘twin epidemic’ of opioids and psycho-stimulants, combined with limited intervention resources, presents an acute challenge for public health and may crucially undermine actively extensive efforts to reduce opioid-related health harms in North America.