The prefrontal cortex (PFC) is a higher order cognitive center that regulates diverse functions like learning, memory, emotion, reward, executive function, and even pain processing, via a descending inhibition on the spinal cord. Not surprisingly, the PFC is implicated in many neurological and psychiatric disorders, some of which are genetically inflicted, while some are adaptive or complex. Yet, molecular mechanisms underlying PFC disorders have been difficult to comprehend owing to the complexity of cell types, circuits and functions of this region, making it extraordinarily challenging to contemplate specificity in therapeutic targeting. However, biochemical, morphological or electrical heterogeneity of neurons, which underlie this complexity, must emerge from their discrete molecular compositions. We asked whether the diversity of cell types (and functions) can be reconciled by mapping their transcriptomic compositions. Using a combination of single cell sequencing and spatial transcriptomics (MERFISH or Multiplexed Error Robust Fluorescence in situ hybridization) we decoded the remarkable molecular diversity of PFC neurons and their discrete anatomical organization patterns along the antero-posterior and dorsal-ventral axes. Distinct cellular and transcriptional features emerged, characterizing the PFC relative to its adjoining cortical areas. Dramatic transcriptional changes were observed across neuronal subtypes during adolescence, when postnatal plasticity peaks in PFC, revealing distinct expression and regulation of several GWAS candidate genes for major neuropsychiatric disorders. By generating cell type specific Cre mouse lines, we mapped neuronal subtypes and circuits underlying adaptive disorders like chronic pain and drug addiction, in their respective disease models. We are currently investigating the transcriptional and epigenetic changes in these circuits during the disease pathogenesis. Cumulatively, our data indicate that redefining composition and organization through single cell omics is greatly facilitating our understanding of the biology and pathology of the PFC and may enable precisely targeting therapies for specific disorders in the future.