Schizophrenia is a severe neuropsychiatric disorder with a poorly understood etiology and progression. We and other research groups have found that energy metabolic pathways in the CNS are perturbed in many subjects with this disorder. Antipsychotic drugs that generally target neurotransmission are currently used for clinical management of the disorder, although these can also have marked effects on energy metabolism in the CNS and periphery. Recent proteomic and metabonomic studies have shown that molecular pathways associated with brain energy metabolism are altered in both the disorder and by antipsychotic treatments. This review focuses on discussion of these molecular alterations. Increased knowledge in this area could facilitate biomarker identification and drug discovery based on improving brain energy metabolism in this debilitating disorder.