An important, if not the chief, condition for the prolongation of the circulation times of lipid vesicles in vivo is the suppression of macromolecular adsorption onto the surface of such vesicles. This adsorption can be prevented very efficiently by a zone of suitably designed and mobile steric hindrances near the lipid layer surface. Lipid vesicles with such a surface coat, cryptosomes, thus circulate in blood for very long periods of time after systemic applications. Lipid vesicles composed of phosphatidylcholine molecules and of suitable polyoxyethylene (PEG) derivatives of phosphatidylethanolamine, for example, remain in the blood circulation 8-10-times longer than standard liposomes made of phosphatidylcholine only: in mice the half-lives of the former and latter vesicles, after an i.v. administration, are approx. 0.6 h and between 5.9 and 13.8 h, respectively. Vesicle longevity is not destroyed by the phosphatidylcholine chains fluidity. Vesicles consisting of a mixture of distearoylphosphatidylethanolamine-PEG (DSPE-PEG) with distearoylphosphatidylcholine or cryptosomes made of DSPE-PEG and soy-bean phosphatidylcholine, consequently, have a very similar fate in vivo. Furthermore, the cryptosome longevity is not affected directly by the presence of the net charges on the lipid membranes and is little sensitive to the details of the group coupling the PEG-headgroups and the lipidic (hydrophobic) anchor. However, the life-time and the distribution of the stabilized lipid vesicles in vivo depend quite sensitively on the surface density of the sterically active headgroups; often (if not always) the resistance to plasma components adsorption as well as the resulting longevity in vivo both show a maximum near the same lipid/stabilizer molar ratio. Optimum bilayer composition may differ for the different combinations of the main and sterically active membrane components. Its position is probably determined by the variations in the molecular mobility and the effective surface-coverage effects: both must be sufficiently high for the vesicle phagocytosis and accumulation in the reticulohystiocytic system to be suppressed. On the contrary, the bilayer surface hydrophilicity, which hitherto has been believed to be of paramount importance for the liposome longevity in vivo, is per se not relevant for the biological fate of the lipid vesicles, provided that this hydrophilicity exceeds some minimum value.