Although the involvement and plasticity of the mesocorticolimbic dopamine (DA) system in cocaine-induced addiction have been studied extensively, the role of the brainstem cholinergic system in cocaine addiction remains largely unexplored. The laterodorsal tegmental nucleus (LDT) contains cholinergic neurons that innervate the ventral tegmental area (VTA) and is crucial for regulating the activity of VTA DA neurons, implying that LDT may also be associated with cocaine addiction. In this review, we summarize our recent findings showing that cholinergic transmission from the LDT to the VTA is involved in acquisition and expression of cocaine-induced conditioned place preference and that, after repeated cocaine exposures, these neurons exhibit synaptic plasticity, which is dependent on NMDA receptor activation, nitric oxide production, and the activity of medial prefrontal cortex. The findings strongly suggest that LDT cholinergic neurons may critically contribute to developing cocaine-induced addiction.