Schizophrenia (SZ) is a devastating psychiatric condition affecting numerous brain systems. Recent studies have identified genetic factors that confer an increased risk of SZ and participate in the disease etiopathogenesis. In parallel to such bottom-up approaches, other studies have extensively reported biological changes in patients by brain imaging, neurochemical and pharmacological approaches. This review highlights the molecular substrates identified through studies with SZ patients, namely those using top-down approaches, while also referring to the fruitful outcomes of recent genetic studies. We have subclassified the molecular substrates by system, focusing on elements of neurotransmission, targets in white matter-associated connectivity, immune/inflammatory and oxidative stress-related substrates, and molecules in endocrine and metabolic cascades. We further touch on cross-talk among these systems and comment on the utility of animal models in charting the developmental progression and interaction of these substrates. Based on this comprehensive information, we propose a framework for SZ research based on the hypothesis of an imbalance in homeostatic signaling from immune/inflammatory, oxidative stress, endocrine and metabolic cascades that, at least in part, underlies deficits in neural connectivity relevant to SZ. Thus, this review aims to provide information that is translationally useful and complementary to pathogenic hypotheses that have emerged from genetic studies. Based on such advances in SZ research, it is highly expected that we will discover biomarkers that may help in the early intervention, diagnosis or treatment of SZ.