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The ventral striatum (nucleus accumbens) and its role in mood, reward, and motivation has been the focus of significant research. Despite this interest, little work has addressed cell type–specific distinctions in medium spiny neurons (MSNs), the main projection neurons in the nucleus accumbens and dorsal striatum, and their function in relation to stress and depression. Previous work has shown opposing roles for D₁ and D₂ receptor MSN subtypes in depression-like outcomes to stress, particularly in regard to repeated neuronal stimulation and excitatory transmission. Yet the mechanisms of action are still unknown. We discuss potential mechanisms by which MSN subtype function promotes dichotomous behavioral outcomes caused by differences in cellular plasticity, subcellular signaling pathways, and genetic expression. This review aims to address our current understanding about the role of nucleus …