Across human and nonhuman species, early indications of an impulsive nature are strongly prognostic of later-onset externalizing problems including delinquency, aggressiveness, and harmful substance use. Accordingly, the development of methods for effectively assessing trait impulsivity has been an important scientific focus for nearly a century. One particularly fruitful research approach has been to examine neurobiological variables derived from simple cognitive or behavioral tasks as potential indicators (biomarkers) of the dispositional liability for impulse-related problems—termed ‘general externalizing proneness.’ Available evidence indicates that influences such as low reward sensitivity and overreactivity to drug cues contribute to substance-related expressions of externalizing proneness by disrupting cognitive-control processes that inhibit impulses and promote adaptive behavior. Owing to such influences, initial substance consumption driven by pursuit of pleasurable effects can give rise to weakened behavioral control and persistent, harmful use, with consequent impairments in functioning. In this chapter, we consider what is currently known about substance problems as an expression of general externalizing proneness, with an emphasis on the role of low inhibitory control and reward dysfunction in such problems. Our main focus is on findings from human studies, but we include mention of parallels in the animal literature that underscore the value of cross-species research in advancing understanding of impulse-related problems and devising methods for preventing and ameliorating them.