Smoking represents one of the greatest preventable causes of death globally, and pharmacological treatments of higher efficacy targeting smoking cessation are necessary. Current drug interventions show only modest success rates and do not adequately address nicotine withdrawal-induced anxiety that is heavily implicated in relapse and failed quit attempts. The purpose of this paper is to highlight that nicotine dependence is at least partially maintained through the negative reinforcing effect of avoiding abstinence-induced anxiety. This paper presents findings which suggest that this effect is mediated by the activation of the Corticotropin Releasing Factor (CRF) system are presented and the implications of a therapeutic agent containing a CRF_1 antagonistare discussed.