Ethanol and nicotine can modulate the activity of several neurotransmitter systems and signalling pathways. Interactions between ethanol and nicotine can also occur via common molecular targets including nicotinic acetylcholine receptors (nAChRs). These effects can induce molecular and synaptic adaptations that over time, are consolidated in brain circuits that reinforce drug-seeking behavior, contribute to the development of withdrawal symptoms during abstinence and increase the susceptibility to relapse. This chapter will discuss the acute and chronic effects of ethanol and nicotine within the mesolimbic reward pathway and brain circuits involved in learning, memory, and withdrawal. Individual and common molecular targets of ethanol and nicotine within these circuits are also discussed. Finally, we review studies that have identified potential molecular and neuronal processes underlying the high incidence of ethanol and nicotine co-use that may contribute to the development of ethanol and nicotine co-addiction.