Nicotine dependence is a construct used to classify a cluster of symptoms and behaviors, a syndrome. It is typically associated with heavy consumption of tobacco products, compulsive use, tolerance, regulation of intake, and withdrawal. Nicotine withdrawal and its associated symptoms, which emerge when nicotine consumption is reduced or ceased (ie, during a quit attempt), are typically regarded by smokers as the greatest barrier to quitting. Indeed, nicotine dependence, nicotine withdrawal, as well as the finding that most smokers attempting to quit fail to do so demand further understanding to enable improved treatment approaches and outcomes. This chapter provides an overview of how nicotine dependence develops, its clinical manifestations, the multifaceted nature of withdrawal, and the influential role of negative affect.