Focal adhesion kinase (FAK) and its related kinase, proline rich tyrosine kinase 2 (PYK2), are major kinases activated by cell-extracellular matrix adhesion. Although they are highly expressed in the nervous system, the functions of these two kinases in the nervous system remained unclear until recently. FAK and PYK2 appear to play an important role in developing nervous system as well as adult brain. Importantly the two kinases are activated by different extracellular stimuli and execute distinct regulatory effects on various aspects of neural developmental processes and neuronal function. This review summarizes the potential roles of FAK and PYK2 in axon path-finding and synaptic plasticity.