Attention-deficit/hyperactivity disorder (ADHD) and tobacco smoking are among the most common and costly psychiatric and behavioral problems. The rates of co-occurrence of these two common problems are larger than expected by chance. Despite progress in identifying the neural and genetic substrates of each, the mechanisms underlying the high rates of comorbidity between ADHD and smoking remain largely unknown. We propose that ADHD and smoking involve dysregulation of dopaminergic and nicotinic-acetylcholinergic circuits and that these aberrations are likely to arise, at least in part, from genetic variations. This review describes an integrative model of the ADHD–smoking comorbidity, with an emphasis on shared neuropharmacological mechanisms. We first describe the prevalence of smoking among ADHD patients. We then describe how ADHD influences stages of smoking behavior (e.g., initiation, maintenance, and relapse). We review common potential genetic substrates of ADHD and smoking, focusing on genes that regulate monoaminergic neurotransmission. We review the behavioral and neuropharmacological bases of smoking and ADHD, focusing on the modulatory roles of nicotine on attention and behavioral control. Finally, we discuss the implications of this model for prevention and clinical outcomes.