Exosomes are membrane nanovesicles implicated in cell-to-cell signaling in which they transfer their molecular cargo from the parent to the recipient cells. This role essentially depends on the exosomes' small size, which is the prerequisite for their rapid migration through the crowded extracellular matrix and into and out of circulation. Here we report much lower exosome mobility than expected from the size of their vesicles, implicate membrane proteins in a substantially impeded rate of migration, and suggest an approach to quantifying the impact. The broadly distributed excess hydrodynamic resistance provided by surface proteins produces a highly heterogeneous and microenvironment-dependent hindrance to exosome mobility. The implications of the findings on exosome-mediated signaling are discussed. (C) 2018 Elsevier Inc. All rights reserved.