Dysfunction in the prefrontal cortex (PFC) has been implicated in the etiology of several late-onset neuropsychiatric disorders. The laminar structure of the PFC is established in utero, but extensive remodeling continues into adolescence. The large-scale pattern of gene transcription during post-natal development was examined in murine PFC using oligonucleotide microarrays. The observed trajectory of mRNA transcript changes during development was consistent with known morphological and biochemical events in this period. Overall, most mRNA levels decreased post-natally with the majority of change between weeks 2 and 4. The mRNA levels of genes involved in cell proliferation decreased substantially in the first 2 post-natal weeks, as post-mitotic cells in the PFC begin to differentiate. Rapid changes in mRNA levels of cytoskeletal, extracellular matrix, plasma membrane lipid, transport machinery, protein folding and regulatory genes were observed. Quantitative PCR verified the microarray results for six selected genes: Dnmt3a, Col3a1, Slc16a1, Mlp, Nid1 and Bdh.