The brain is now recognized as an insulin-sensitive organ. The brain not only responds to circulating insulin but also takes it up. The blood–brain barrier (BBB) lies at the interface between the brain and the circulation and thus, not only mediates the transport process from blood to brain but also initiates intracellular signaling events. Despite these advancements and wide recognition of events, there is still debate about whether brain insulin is solely derived from a pancreatic source, how insulin enters the brain, and the effects of signaling at brain endothelial cells (BECs). This chapter will focus on what is known about insulin and the interactions at the BBB.