Reward seeking is controlled by conditioned stimuli (CSs). There is a positive relation between mesocorticolimbic dopamine (DA) and the performance of learned reward-directed behavior. The mechanisms by which reward-, including drug-, associated stimuli come to acquire the capacity to activate the DA systems are not fully understood. In this review, we discuss the possible neurochemical mechanisms within the ventral tegmental area that may be involved in how CSs acquire the capacity to activate ventral tegmental area (VTA) DA neurons based on principles of long-term potentiation in the VTA and the role of mesocorticolimbic DA in reward-related learning. We propose that CSs function as such because they acquire the capacity to activate VTA DA neurons. Furthermore, CSs come to acquire this control of VTA DA cells when there is coincident N-methyl-d-aspartate receptor stimulation on VTA DA cells and strong depolarization of VTA DA cells, possibly by muscarinic acetylcholine receptor stimulation on these cells. This coincident activity leads to the strengthening of CS-associated glutamatergic synapses and the control by CSs of mesocorticolimbic DA systems and reward-directed behavior.