The article reviews the role of the default-mode network (DMN) in cognition and disease. The DMN, a set of brain regions active during unengaged mental states, is known to deactivate during focused attention. The review highlights the functional significance of DMN suppression in goal-directed cognition, suggesting that it helps reduce irrelevant functions like mind-wandering. Studies show that lower DMN activity is associated with better performance on tasks requiring external attention. The review also discusses the implications of DMN suppression deficits in severe mental illnesses, such as schizophrenia and depression, where DMN over-activity may contribute to cognitive impairments. Pharmacological neuroimaging studies using ketamine and other agents have provided insights into the synaptic mechanisms underlying DMN suppression, including the role of glutamatergic and monoaminergic neurotransmission. The authors propose a computational model to explain the dynamics of DMN suppression during cognitive operations, emphasizing the importance of optimal inhibitory microcircuit function.The article reviews the role of the default-mode network (DMN) in cognition and disease. The DMN, a set of brain regions active during unengaged mental states, is known to deactivate during focused attention. The review highlights the functional significance of DMN suppression in goal-directed cognition, suggesting that it helps reduce irrelevant functions like mind-wandering. Studies show that lower DMN activity is associated with better performance on tasks requiring external attention. The review also discusses the implications of DMN suppression deficits in severe mental illnesses, such as schizophrenia and depression, where DMN over-activity may contribute to cognitive impairments. Pharmacological neuroimaging studies using ketamine and other agents have provided insights into the synaptic mechanisms underlying DMN suppression, including the role of glutamatergic and monoaminergic neurotransmission. The authors propose a computational model to explain the dynamics of DMN suppression during cognitive operations, emphasizing the importance of optimal inhibitory microcircuit function.