Dopamine-containing neurons originating in the ventral tegmental area project primarily to the nucleus accumbens and the prefrontal cortex, forming the mesolimbic and mesocortical systems, respectively. Virtually every drug of abuse influences dopamine-mediated neurotransmission by affecting directly or indirectly the activity of these cells. Amphetamine and cocaine, in addition to opioids and nicotine, induce short- and long-term modifications of firing in the dopamine-containing neurons of the ventral mesencephalon. Although exposure to psychostimulants mainly depresses neuronal activity, nicotine and morphine enhance neuronal activity. However, under particular conditions, these drugs could cause different changes of firing. In this article, we propose that changes in the activity of dopamine-containing neurons are related to the processes of addiction. Therefore, we suggest that both the modulation of dopamine release in the extracellular space and transient or enduring changes in the firing of dopamine-containing neurons could be associated with important features of drugs of abuse.