There is a strong association between tobacco smoking and the consumption of alcoholic beverages. When compared to the effects of either drug on its own, the combined use may lead to worsened outcomes, such as less successful quitting attempts and increased likelihood of developing mood disorders. Co-consumption most frequently begins during adolescence, a developmental period that is characterized by an increased risk for substance use disorders. However, to date, most studies that have contributed to the current state of knowledge on the mechanisms that underlie tobacco or alcohol use/abuse, and their consequences, adopted adult animal models. Besides, the available literature hardly addresses the effects of co-exposure, irrespective of age. Since adolescence is a period of transition between infancy and adulthood that is characterized by unique brain maturational events and behavioral traits, the mechanisms that drive drug use/abuse in adolescents differ in several aspects from those proposed to underlie adult consumption. This review summarizes and consolidates recent findings on common molecular targets and neuropharmacological mechanisms of action associated with nicotine/tobacco smoke and ethanol co-exposure in animal models, highlighting the effects that culminate in behavioral dysfunctions. To that effect, we discuss the role of mesocorticolimbic system maturation events, cross-tolerance and cross-reinforcement, stress, and sex differences in the context of adolescent co-exposure, identifying gaps in knowledge regarding the interactions between these habit-forming drugs. Finally, we suggest future directions for research on epigenetic mechanisms associated with nicotine and ethanol co-exposure as well as on potential pharmacological therapies for co-addiction.