Great neuroanatomists of the twentieth century rec- ognized that the cerebral cortex of mammals is the single most complex structure of the central nervous system both in terms of neuronal diversity and con- nectivity. Understanding the cellular and molecular mechanisms specifying the afferent and efferent con- nectivity in the neocortex may seem like a daunting task. However, recent technical advances have greatly improved our ability to (1) profile gene expression of neuronal populations isolated based on their connec- tional properties, (2) manipulate gene expression in specific neuronal populations, and (3) visualize their ax- onal projections in vivo. These new tools are revolution- izing our ability to identify the molecular mechanisms patterning afferent and efferent cortical projections.