The objective of this paper is to identify the principal blood components governing the fate of liposomes in blood circulation. Information based on an isolated perfused liver system in rats has revealed the central role of the complement system in enhancing the uptake of liposomes by the liver. A species difference was an important factor in determining the uptake mechanisms of liposomes by the liver. Limited evidence revealed the tendency that opsonin-dependent hepatic uptake is principal in rats, while opsonin-independent or dysopsonin-dependent uptake governs in mice, although there are some exceptions. These studies provide us with important information for understanding the uptake mechanisms of liposomes by the liver, and useful insights in predicting the in vivo disposition of liposomes in humans.