Liposomes have gained increased attention as systemic drug delivery vehicles following recent regulatory approvals of several vesicle-formulated drugs. These products have demonstrated improved therapeutic indices over their corresponding conventional drugs by avoiding sensitive tissues and/or increasing delivery to specific targets in vivo. They have achieved these improvements primarily through physical means: (1) by retaining drug within vesicles while in the circulation, thus avoiding or minimizing uptake by sensitive normal tissues; and (2) by selectively extravasating into target tissues, releasing active drug. In order to improve upon these therapies in the future, clinically active liposome delivery systems most likely will need to include site-directed surface ligands to further enhance their selective delivery. This may be crucial for the in vivo transport and delivery of macromolecules, including antisense, oligonucleotide aptamers, and genes, which-unlike most conventional drugs-do not circulate well and often require cellular uptake by fusion, endocytosis, or other processes to reach their active sites. This manuscript reviews technologies applicable to directing liposomes and their contents to selected in vivo targets using surface-bound, site-specific ligands. Presented are the biological barriers to be overcome, criteria for selecting the determinants to be targeted, various targeting ligands and overall delivery system design considerations. Several novel targets as well as novel ligand constructs for site-directed therapy are reviewed and discussed. Systemic liposome therapy, which currently must be administered by the intravenous route, is the principal focus of this analysis.