Severe mental illnesses (SMIs), such as schizophrenia and bipolar disorder, are traditionally conceptualized as disorders of the central nervous system (CNS). Growing evidence, however, suggests that SMIs may be better understood as multisystem disorders, characterized by metabolic and immune dysregulation affecting both brain and body. In this chapter, the hypothesis that psychiatric symptoms may emerge because of systemic metabolic dysfunction is explored. Evidence is presented to show that metabolic abnormalities—including insulin resistance, dysglycemia, and immune activation—are present from onset of SMI, and that these abnormalities may contribute to core psychiatric symptoms such as amotivation, cognitive impairment, anhedonia, and neurovegetative alterations. The role of insulin and cytokine signaling pathways is discussed, with a focus on their reciprocal influence across the CNS and peripheral organs, and the potential intrinsic and extrinsic modulators of these pathways, including sex, stress, and nutrition, are outlined. A conceptual framework is proposed in which SMIs are understood as manifestations of dysregulated energy allocation and metabolic stress. Finally, a research strategy is outlined to investigate peripheral metabolic signatures as tools for stratification, prognosis, and treatment in SMIs, with the goal of advancing a precision medicine approach to psychiatric care.