Nicotine use and social stress have a complex interplay, which has been shown to be mediated by cholinergic neurons in the ventral tegmental area (VTA). Social stress is often comorbid with nicotine consumption, and the presence of either stress or nicotine use significantly increases the risk of developing the other. In fact, it has been shown in mice that nicotine injection is sufficient to increase susceptibility to social defeat, a reliable model for stress and anxiety-like behavior. Stressful events can molecularly remodel cholinergic synapses, inducing the production of more cholinergic transporters and increasing the number of nicotinic receptor binding sites. One way stress and nicotine remodel cholinergic synapses are through long-term potentiation (LTP) in cholinergic pathways in the VTA, enhancing the experience of stress and the effects of addiction. Despite both primarily acting on the ????7 subtype nicotine receptor, nicotine and stress induce LTP in vastly different ways: nicotine acts quickly via ligand-gated ion channels while stress activates a slower hormonal-induced G-protein coupled receptor pathway. These findings suggest that dopaminergic VTA neurons may be a useful therapeutic target for depression, anxiety, and other stress-related disorders. Deep brain stimulation has preliminarily shown to be a potential therapeutic treatment for untreatable depression, especially when it targets the medial forebrain bundle within the VTA-NAc pathway. Sleep patterns are also partially regulated by dopaminergic VTA neurons, and sleep deficits may contribute to social stress and other depressive symptoms. The role of nicotine dependence in stress-related mental illnesses is especially important to consider given the recent increase in adolescent nicotine use with the advent of vaping. Adolescents already have an increased risk for developing mental illnesses, and it is important that young people are made aware of the potential psychological harms of nicotine use.