<p>Stimulant Use Disorder (StUD) is a pervasive and extremely dangerous form of addiction for which there are currently no approved medications. Discovering treatments will require a deep understanding of the neural mechanisms underlying the behavioral effects of stimulant drugs. A major target is the mesocorticolimbic system. Individual differences in mesocorticolimbic function can influence the propensity to initiate stimulant use and the risk for stimulant use disorders. Since repeated stimulant use can further alter mesocorticolimbic function, these pathways may serve as a target for both early interventions aimed at preventing the onset of harmful stimulant use and treatments designed to alleviate addiction symptoms. Here we review evidence from studies in both humans and laboratory animals, focusing on the neurotransmitter systems most strongly implicated in StUD, primarily dopamine and, to a lesser extent, glutamate. We identify evidence of (i) complex, non-linear perturbations to mesocorticolimbic function related to stimulant use, and (ii) gaps in knowledge and opportunities for research to improve our understanding of the determinants and consequences of StUD.</p>