We reviewed the morphological characteristics and physiological functions of hepatic sinusoidal endothelial cells (SECs) and Kupffer cells (KCs), both of which are major components of the hepatic sinusoid, and we showed the implication of these hepatic sinusoidal lining cells in the pathophysiology of the liver, based on our experimental studies. The most outstanding feature of SECs is that they are provided with numerous fenestrae, thereby allowing direct communication between the sinusoidal lumen and the space of Disse. Physiologically, SECs play a role in filtration function, endocytic function, and putative participation in the regulation of sinusoidal blood flow. As for KCs, they account for major portion of fixed macrophages in the entire body, and exhibit vigorous activity for phagocytosis, and produce many kinds of soluble mediators such as cytokines, prostanoids, oxygen radicals, and proteases. To determine whether these cells are implicated in pathophysiological processes in the liver we directed our attention to liver injury associated with sepsis and cold-preservation injury of liver tissue. In a septic rat model, we found that when KCs that included hepatic macrophages were activated, they released excess tissue-toxic mediators, probably leading to SEC damage. In the cold-preserved liver,we demonstrated that KCs were functionally activated and that the morphology of SECs was destroyed. When the liver was reperfused with plasma and a leucocyte suspension, hypercoagulability and increased leucocyte adherence occurred. In both experimental models, we demonstrated that KC blockade ameliorated the liver injury, and this was associated with the morphological improvement of SECs. Thus, we showed the pathogenetic implication of KCs and SECs, due possibly to microcirculatory disturbance in the hepatic sinusoid, and further emphasized the involvement of activated KCs in SEC impairment.