Increasing evidence indicates that substance-dependent individuals (SDI) are impaired in executive control tasks relying on different systems within the prefrontal cortex (PFC). Three different functional systems have been described: the dorsolateral prefrontal cortex (DLPC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) circuits. Dysfunction within each PFC system is associated with different behavioral, cognitive, and emotional abnormalities. Few studies have conducted an exhaustive examination of all these different factors in SDI. In this study, SDI (including alcohol, cocaine, and methamphetamine polysubstance users, n = 35) were compared with healthy controls (n = 36) on a series of behavioral (Frontal Systems Behaviour Scale, FrSBe), cognitive (N-back, Go-No Go, and Wisconsin Card Sorting Tasks), and emotional (International Affective Picture System, IAPS) tasks, each of which was thought to tax a different component of these PFC functional systems. SDI showed greater behavioral problems in the apathy, disinhibition, and executive dysfunction subscales of the FrSBe. Behavioral deficits were significantly associated with several real-life domains in which SDI typically have problems. SDI also showed poorer performance on cognitive tests of working memory, response inhibition and mental flexibility, and abnormal processing of affective images from the IAPS. Cognitive, behavioral, and emotional measures were moderately correlated.This study was conducted in the Department of Neurology, University of Iowa, Iowa City, USA (JINS, 2006, 12, 405–415.)