The liver is the largest organ in the body and, in humans, weighs between 1,400 and 1,600 g (2.5% of total body weight). It receives 25% of the total cardiac output, which arrives via the hepatic artery (one-third of hepatic blood flow) and the portal vein (two-thirds of hepatic blood flow). Blood flows through liver sinusoids, a unique microvasculature that consists of plates of liver sinusoidal endothelial cells (LSECs) between plates of hepatocytes, before coming in contact with the liver parenchyma. LSECs account for 20% of total liver cells (an estimated 1 × 108 cells) whereas hepatocytes represent the majority of liver cells (estimated 60% or 3 × 108 cells). The remaining cell populations are (a) hepatic stellate cells (HSCs) (5%–8%), which are liver-specific pericytes; (b) biliary epithelial cells, also known as cholangiocytes, which line the bile ducts; and (c) macrophages called Kupffer cells. LSECs are unique in comparison to other organs in that they possess multiple fenestrae (pores) arranged in sieve plates (Figure 66.1) and lack an organized basement membrane. LSECs lie in close proximity to hepatocytes, and the interaction of these two cell types has been the subject of intense study. Cellular cross-talk between LSECs and hepatocytes plays an important role in homeostasis and physiologic processes such as liver organogenesis and liver regeneration. Moreover, abnormalities in intercellular communication underlie virtually every disease of the liver, including acute and chronic inflammatory liver disease, liver fibrosis, and hepatocarcinogenesis. Of these physiological and pathological states, liver regeneration is the most studied and best understood. Thus, this chapter focuses primarily on the latter model as a means to explore the biology of hepatocyte–endothelial cell (EC) interactions.