Of fundamental importance in the design of a therapeutic drug carrier system is a thorough understanding of the factors which control its fate in the living animal. The use of liposomes as a carrier system able to improve the therapeutic efficacy of a wide range of drugs, requires manipulation of its physical characteristics, thereby influencing in vivo behavior. This review brings together findings of recent studies which describe how liposomal stability and clearance in vivo are controlled by the architecture of the vesicles themselves which in turn, via interaction with humoral factors, controls the fate in terms of tissue distribution of the carrier and its contents. Based on these studies, a rationale for liposome design aimed at in vivo drug delivery is discussed.