Since constant perfusion of blood throughout the brain is critical for neuronal health, the regulation of cerebral blood flow is complex and highly controlled. This regulation is controlled, in part, by the cerebral endothelium. In this review, multiple modes of endothelium-derived blood flow regulation is discussed, including chemical control of vascular tone, heterotypic and homotypic cell-cell interactions, second messenger signaling, and cellular response to physical forces and inflammatory mediators. Because cerebral small vessel disease is often associated with endothelial dysfunction and a compromised blood-brain barrier, understanding the endothelial factors that regulate vessel function to maintain cerebral blood flow and prevent vascular permeability may provide insights into disease prevention and treatment.