Most neuropsychiatric diseases involve multifactorial systems characterized by complex interactions among genetic predisposition/resiliency, environmental/social determinants, molecular sequelae and brain network organization. The allostatic load affects remodeling of brain architecture and physiological processes in response to stressors. The epigenetic allostasis emphasizes the influence of early-life experiences on the development of neuropsychiatric pathology in susceptible individuals. This presentation will cover the neurobiological frameworks underlying three main components of allostatic load – oxidative stress, inflammation and insulin resistance (IR) while accounting for genetic (familial) and epigenetic (early-life trauma) in human models.