Endothelial cells form a continuous single layer lining throughout the vascular tree. Such positioning allows the endothelium to monitor numerous environmental signals within the blood vessel, including blood composition, structural matrix, and blood flow dynamics. Following signal integration, endothelial cells then induce context-specific changes in vessel properties. The nonreceptor tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2) are activated by integrins, growth factors, and mechanical stimuli, suggesting a potentially important role in the integration of environmental stimuli. This review will explore the current understanding of FAK and Pyk2 signaling in endothelial regulation of vascular function.