Pyramidal cells in cortical Layers 5 and 6 are the only cells in the cerebral cortex with axons that leave the cortex to influence the thalamus. Layer 6 cells provide modulatory feedback input to all thalamic nuclei. Layer 5 cells provide driving input to higher-order thalamic nuclei and do not innervate first-order nuclei, which get their driving inputs from subcortical sources. Higher-order nuclei innervated by Layer 5 cells thus seem to be involved with cortico-thalamo-cortical communication. The Layer 5 axons branch to also target additional subcortical structures that mediate interactions with the external environment. These corticofugal pathways represent the only means by which the cortex influences the rest of the neuraxis and thus are essential for proper cortical function and species survival. Here we review current understanding of the corticofugal pathways from Layers 5 and 6 and speculate on their functional contributions to neural processing and behavior.