This article reviews the disposition of intravenously injected phospholipid liposomes and discusses the problems related to its kinetic modeling. The processes responsible for the plasma clearance of liposomes are examined in detail and it is shown that mechanisms other than reversible distribution to the extravascular space are, as a rule, responsible for the biphasic plasma clearance patterns that are typically observed following bolus intravenous injection of liposomes. Accordingly, a one-compartment open model is generally sufficient to describe the disposition kinetics of phospholipid vesicles. Two factors may be responsible for the observation of a biphasic decline of plasma liposome concentration. The first factor is the presence of different liposomal species with different kinetic behaviors. Kinetically distinct vesicles are present in preparations of liposomes that are heterogeneous in size, since the larger vesicles are cleared at a faster rate than the smaller ones. Different liposomal species may also originate in the plasma as a result of: i) fusion between phospholipid vesicles with generation of larger liposomal structures; and ii) interaction with high-density lipoproteins (HDL) with consequent production of either liposomes that have acquired apoproteins or lipoprotein particles enriched in phospholipids. Both these species are cleared by specific mechanisms at rates different from that of the original vesicle. The second factor is a time-dependent decrease in clearance due to progressive saturation of the retention capacity of the cells that take up liposomes. A convex concentration-time decay curve has also been reported. This decay pattern is consistent with a concentration (dose)-dependent elimination. As this observation relates to only one type of liposome (small unilamellar vesicles composed of sphingomyelin and cholesterol), its relevance to the disposition of liposomes of different size and composition remains to be established.