Recent reports indicate that stimulant-related deaths are increasing dramatically. People who die from acute stimulant toxicity have high rates of pre-existing cardiovascular disease (CVD), much of which is undiagnosed. Moreover, people who use stimulants with CVD often remain asymptomatic until presenting to an emergency department with an acute event. Prior research shows that symptoms of stimulant toxicity may occur on a regular basis, and that people who die from stimulant toxicity are older than those who die of opioid toxicity. Taken collectively, the existing evidence suggests that death from acute stimulant toxicity is often an outcome of long-term, cumulative exposure leading to cardiovascular dysfunction rather than acute intoxication. Strategies tailored to the distinct etiology of stimulant overdose are needed. We propose a three-part approach including (1) implementing stimulant use interventions that promote not only abstinence, but also use reduction, (2) treating ongoing stimulant use as a chronic cardiovascular condition, and (3) making stimulant toxicity interventions relevant to the populations most affected, which includes people outside of the traditional health-care system. In short, to reduce stimulant-related fatality, we need to transform our approach in ways that are tailored to address its natural history.