The efficient use of retrovirus and lentivirus vectors for in vivo gene delivery in gene therapy applications will be greatly facilitated by improved methods to characterize the bio-distribution and fate of the vectors after systemic administration and to understand the mechanisms that determine tissue tropism of vectors in vivo. We have been developing methods to detect virus particles in vivo that take advantage of the existence of the cell-derived membrane that the viruses acquire in the process of budding from producer cells. We have labeled virus particles with a fluorescent membrane marker and studied factors affecting the distribution and virus particle attachment to a variety of tissues, especially the vascular endothelium and the liver, after systemic administration of the fluorescent-tagged virus particles. Systematically delivered virus is rapidly cleared from the circulation concomitant with rapid uptake into tissues of the reticuloendothelial system, particularly the liver and spleen. Fluorescent particles are also found to associate with the microvascular endothelium by mechanisms that may involve P-selectin.