Psychostimulant addiction is an important, relapsing condition for which there is no effective pharmacological treatment. Countering this problem requires an understanding of the specific risk factors that predispose individuals to initial misuse of these drugs. Healthy individuals display marked individual differences in emotional, behavioral and brain responses to low and moderate doses of stimulant drugs. These between-person differences have been most often studied using personality measures of sensation seeking. However, a growing body of work in healthy adults indicates potentially unique sources of variance in these responses that are related to four dissociable personality domains: extraversion, fearlessness, impulsivity and absorption. These four domains are empirically dissociable and can serve as endophenotypic markers of dopamine, norepinephrine and serotonin function in healthy individuals. The relationship between normal variation in these traits and the pharmacological effects of these drugs is here proposed as a framework for better understanding the specific sources of between-person variation in stimulant drug effects on mood, behavior and brain responses in healthy humans.