Ligand-targeted nanomedicines, particularly those directed to vascular-accessible biomarkers,1,2 have evolved from fanciful concepts 25 years ago to product concepts now near or in clinical trials. While numerous chemical and biological barriers have been discovered and broached over this time frame, perhaps the single greatest challenge to success of nanomedicine technologies has been their inefficient access to extravascular constituents. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Serrano et al delineates the unique and complex cell biology surrounding ICAM-1 mediated intracellular (and presumably) transcellular delivery of nanoparticles up to 4.5 µm, and illustrates a close mechanistic similarity to leukocyte endothelial transmigration. See accompanying article on page 1178 Many have touted the concept of enhanced permeability and retention as a mechanism for nanoparticle delivery into tumors and inflammatory sites through a purportedly leaky vasculature.3,4 Considerable research, particularly studies conducted in subcutaneous mouse tumor models, has demonstrated this effect over the last decade, but the magnitude of the extravascular delivery has depended on high intravascular overdosing of agents, prolonging particle systemic half-life (eg, pegylation), and decreasing particle size.5 Unfortunately, clinical hope for the enhanced permeability and …