Smoking is the major cause of preventable deaths worldwide, and although there is a decline in overall smoking prevalence in developed countries, the decline in women is less pronounced than in men. Women become dependent faster and experience greater difficulties in quitting. Similar trends have been observed in animal models of nicotine/tobacco addiction. Individual differences in vulnerability to drug abuse are also observed in nicotine/tobacco addiction and point to the importance of sex differences. This Review, summarizes findings from three experimental approaches used to depict nicotine preference in animal models, intravenous and oral nicotine self-administration and nicotine-induced conditioned place preference. Nicotine preference is considered to be reflected in the animal's motivation to administer the drug (intravenously or orally) or to prefer an environment paired with the presence of the drug (conditioned place preference). These approaches all point to the importance of sex and age of the subjects; the preference of females and adolescents appear to be more pronounced than that of males and adults, respectively. A closer look at these factors will help us understand the mechanisms that underlie nicotine addiction and develop strategies to cope. Ignoring sex differences and reaching conclusions based only on studies using male subjects has resulted in erroneous generalizations in the past. Sex differences in nicotine preference have been clearly documented, and awareness on this aspect of nicotine dependence will significantly impact our success in translational research. (C) 2016 Wiley Periodicals, Inc.