Glial cells play a critical role in neuronal function, mood disorders, and drug addiction. This review highlights the contributions of neurotrophic factors, neuroinflammation, and gut microbiota to these conditions. Specific glial cell types, including microglia, astrocytes, oligodendrocytes, and synantocytes, are emphasized for their roles in the phenotypic manifestations of mood disorders and drug addiction. The review also discusses the potential for developing novel therapeutics based on this knowledge. Major depressive disorder (MDD) is influenced by neurotrophic factors like BDNF, which modulate neuronal differentiation, growth, and plasticity. Neuroinflammation, involving pro-inflammatory cytokines and microglial activation, is also linked to MDD. Gut microbiota dysbiosis can affect neurotransmitter balance and neuroinflammation, contributing to MDD. Drug addiction involves changes in brain circuits controlling reward and stress responses. Neurotrophic factors and neuroinflammation are key factors in drug addiction, with BDNF and glial cell-derived neurotrophic factor (GDNF) playing roles in modulating drug-seeking behavior. Neuroinflammation, driven by microglial and astrocytic activation, contributes to addiction-related brain and behavioral deficits. Glial cells, including microglia, astrocytes, oligodendrocytes, and synantocytes, are essential for maintaining brain homeostasis, myelination, and synaptic function. Microglia regulate neuroinflammation and are involved in the pathophysiology of MDD and drug addiction. Astrocytes support neuronal function, regulate the blood-brain barrier, and are involved in synaptic plasticity. Oligodendrocytes contribute to myelination and white matter integrity, which are disrupted in MDD and drug addiction. Synantocytes (NG2 cells) are involved in neuroinflammation and neurovascular unit formation, and may play a role in mood disorders. Understanding the roles of glial cells in these conditions may lead to novel therapeutic strategies targeting glial receptors and enzymes. This review provides an update on glial-neuron interactions in MDD and drug addiction, emphasizing the potential for novel interventions.Glial cells play a critical role in neuronal function, mood disorders, and drug addiction. This review highlights the contributions of neurotrophic factors, neuroinflammation, and gut microbiota to these conditions. Specific glial cell types, including microglia, astrocytes, oligodendrocytes, and synantocytes, are emphasized for their roles in the phenotypic manifestations of mood disorders and drug addiction. The review also discusses the potential for developing novel therapeutics based on this knowledge. Major depressive disorder (MDD) is influenced by neurotrophic factors like BDNF, which modulate neuronal differentiation, growth, and plasticity. Neuroinflammation, involving pro-inflammatory cytokines and microglial activation, is also linked to MDD. Gut microbiota dysbiosis can affect neurotransmitter balance and neuroinflammation, contributing to MDD. Drug addiction involves changes in brain circuits controlling reward and stress responses. Neurotrophic factors and neuroinflammation are key factors in drug addiction, with BDNF and glial cell-derived neurotrophic factor (GDNF) playing roles in modulating drug-seeking behavior. Neuroinflammation, driven by microglial and astrocytic activation, contributes to addiction-related brain and behavioral deficits. Glial cells, including microglia, astrocytes, oligodendrocytes, and synantocytes, are essential for maintaining brain homeostasis, myelination, and synaptic function. Microglia regulate neuroinflammation and are involved in the pathophysiology of MDD and drug addiction. Astrocytes support neuronal function, regulate the blood-brain barrier, and are involved in synaptic plasticity. Oligodendrocytes contribute to myelination and white matter integrity, which are disrupted in MDD and drug addiction. Synantocytes (NG2 cells) are involved in neuroinflammation and neurovascular unit formation, and may play a role in mood disorders. Understanding the roles of glial cells in these conditions may lead to novel therapeutic strategies targeting glial receptors and enzymes. This review provides an update on glial-neuron interactions in MDD and drug addiction, emphasizing the potential for novel interventions.