Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA) behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis) and six selected F1 hybrids. All rats were trained to press a lever to obtain food starting on postnatal day (PN) 32, and then nicotine (0.03 mg/kg/infusion, i.v.) reinforcement was made available on PN41-42 (10 consecutive daily 2 h sessions). Of the 12 isogenic strains, Fisher rats self-administered the fewest nicotine infusions (1.45 ± 0.36/d) during the last 3 d, while Lewis rats took the most nicotine (13.0 ± 1.4/d). These strains sorted into high, intermediate and low self-administration groups in 2, 2, and 8 strains, respectively. The influence of heredity on nicotine SA (0.64) is similar to that reported for humans. Therefore, this panel of isogenic rat strains effectively models the overall impact of genetics on the vulnerability to acquire nicotine-reinforced behavior during adolescence. Separate groups of rats responded for food starting on PN41. The correlation between nicotine and food reward was not significant. Hence, the genetic control of the motivation to obtain nicotine is distinctly different from food reward, indicating the specificity of the underlying genetic mechanisms. Lastly, the behavior of F1 hybrids was not predicted from the additive behavior of the parental strains, indicating the impact of significant gene-gene interactions on the susceptibility to nicotine reward. Taken together, the behavioral characteristics of this model indicate its strong potential to identify specific genes mediating the human vulnerability to smoke cigarettes.