Adolescents are especially likely to initiate tobacco use and are more vulnerable to long-term nicotine dependence. A unifying hypothesis is proposed based largely on animals studies that adolescents, as compared to adults, experience enhanced short-term positive and reduced aversive effects of nicotine, as well as less negative effects during nicotine withdrawal. Thus, during adolescence the strong positive effects of nicotine are inadequately balanced by negative effects that contribute to nicotine dependence in adults. This review provides a neural framework to explain developmental differences within the mesolimbic pathway based on the established role of dopamine in addiction. This pathway originates in the ventral tegmental area (VTA) and terminates in the nucleus accumbens (NAcc) where dopamine is increased by nicotine but decreased during withdrawal. During adolescence, excitatory glutamatergic systems that facilitate dopamine are overdeveloped, whereas inhibitory GABAergic systems are underdeveloped. Thus, it is hypothesized that adolescents display enhanced nicotine reward and reduced withdrawal via enhanced excitation and reduced inhibition of VTA cell bodies that release dopamine in the NAcc. Although this framework focuses on adolescents and adults, it may also apply to the understanding of enhanced vulnerability to nicotine in adults that were previously exposed to nicotine during adolescence. The hypothesis presented in this review suggests that the clinical diagnostic criteria developed for nicotine dependence in adults, based primarily on withdrawal, may be inappropriate during adolescence when nicotine withdrawal does not appear to play a major role in nicotine use. Furthermore, treatment strategies involving nicotine replacement may be harmful for adolescents because it may cause enhanced vulnerability to nicotine dependence later in adulthood.