For several years we have investigated how neural circuits are formed and maintained through the action of guidance cues that include semaphorin proteins, their classical plexin and neuropilin receptors, and also novel receptors. We employ a cross phylogenetic approach, using both invertebrate and vertebrate model systems, to understand how guidance cues regulate neuronal pathfinding, morphology, and synaptogenesis. We also seek to understand how these signals are transduced to cytosolic effectors. Though broad in scope, our interrogation of the roles played by semaphorin guidance cues provides insight into the regulation of neural circuit assembly and function. Our current work includes a relatively new interest in understanding the origins of laminar organization in the CNS. This direction has resulted in our identification of guidance cues that regulate both specific and general aspects of neurite stratification in the mouse retina, in addition to the targeting of retinal ganglion cell axons to retinorecipient midbrain targets. These observations have prompted us to look for cellular and molecular mechanisms that regulate laminar organization in the mouse neocortex.