Many of the challenges facing nonviral gene therapy, to make it as effective as the viral-based version, have yet to be overcome. The technology possesses sufficient biosafety advantages to make the construction of 'artificial viruses' a worthwhile undertaking. The impact of vehicle architecture on traffic regulation, and the convergence of several intracellular pathways in late endosomes, indicates that the particular intracellular route might be less relevant than formerly believed. Proper functional tuning of artificial viruses by the use of full proteins or protein stretches, and especially, the incorporation of membrane-active peptides, would improve transgene expression levels and convert artificial viruses into powerful tools for gene medicine. © 2008 Elsevier Ltd. All rights reserved.