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The prefrontal cortex (PFC) is essential for developing action plans, driven by the coordination of cognitive and emotional processes, that relies on both current goals and future plans. Importantly, behavioral flexibility is necessary for successfully reaching goals in a changing environment. To accomplish this, the PFC comprises several regions, each of which is associated with various functions. It is the product of evolution that has resulted in a complex set of inter-related structures or regions with networks of connectivity to wide-spread brain regions. These regions are organized into networks to mediate different aspects of behavior. Indeed, it is now well accepted that circuit dysfunction between regions and/or networks underlie most mental illnesses. The goal of this special issue of Neuropsychopharmacology Reviews is to highlight key structural and functional features of PFC that are particularly relevant to the mechanisms that underlie normal and abnormal behaviors.