This article describes recent theoretical developments and empirical findings regarding the role of negative affect (NA) and emotion regulation in nicotine dependence and smoking cessation. It begins with a review of affect-based models of addiction that address conditioning, affect motivational, and neurobiological mechanisms and then describes the role of NA and emotion regulation in the initiation and maintenance of cigarette smoking. Next, the role of emotion regulation, coping skill deficits, depression, and anxiety sensitivity in explaining the relationship between NA and smoking relapse are discussed. We then review recent models of affect regulation, including emotional intelligence, reappraisal and suppression, and emotional acceptance, and describe implications for substance abuse and smoking cessation interventions. Finally, we point out the need for further investigations of the moderating role of individual differences in response to NA in the maintenance of nicotine dependence, and controlled randomized trials testing the efficacy of acceptance-based interventions in facilitating smoking cessation and relapse prevention.