Patterns of association between attention deficit hyperactivity disorder (ADHD) and substance-use disorders are considered. Recent investigations have found that up to 50% of individuals with continuing ADHD symptoms have a substance-use disorder. ADHD appears to represent an independent risk factor for substance abuse. We review clinical challenges posed by the diagnosis of ADHD in substance-abusing populations. Nicotine dependence is also substantially more common among adults with ADHD (40%) than in the general population (26%). While several classes of substances of abuse may ameliorate various symptoms of ADHD, individuals with ADHD may also be vulnerable to substance use because of poor judgment or impulsive behavior in social settings. Evidence is reviewed from genetic studies examining the role of the dopamine D2 (DRD2) gene in the etiology of ADHD. The presence of ADHD may affect the course of adolescent substance abuse in several ways: predicting earlier age of onset, longer duration of substance-use disorder, and progression of alcohol abuse to another drug-use disorder. Individuals with ADHD have been noted to have a shorter interval between the onsets of drug abuse and drug dependence. Such individuals are also at greater risk for treatment failure, as their disruptive behaviors interfere with treatment access and response. Lastly, we review advances in pharmacotherapeutic agents used for treating ADHD and consider the impact of these interventions on comorbid substance-use disorders. We suggest promising areas of focus for clinical research trials targeting the subpopulation of substance abusers with concurrent ADHD.