Drug addiction is characterized by an unhealthy priority for drug consumption with a compulsive, uncontrolled drug-intake pattern due to a disordered motivational system. However, only some individuals become addicted, whereas others maintain regular but controlled drug use. Whether the transition occurs might depend on how individuals process drug relative to nondrug reward. We applied functional magnetic resonance imaging to measure mesocorticolimbic activity to stimuli predicting monetary or cigarette reward, together with behavioral assessment of subsequent motivation to obtain the respective reward on a trial-by-trial basis, in 21 nicotine-dependent and 21 nondependent, occasional smokers. Occasional smokers showed increased reactivity of the mesocorticolimbic system to stimuli predicting monetary reward relative to cigarette reward and subsequently spent more effort to obtain money. In the group of dependent smokers, we found equivalent anticipatory activity and subsequent instrumental response rates for both reward types. Additionally, anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain reward. This imbalance in the incentive salience of drug relative to nondrug reward-predicting cues, in a network that drives motivation to obtain reward, could represent a central mechanism of drug addiction. Copyright 2010 Society of Biological Psychiatry. All rights reserved.