Enhanced permeability of the tumor vasculature allows macromolecules to enter the tumor interstitial space, while the suppressed lymphatic filtration allows them to stay there. This phenomenon - EPR has been the basis of nanotechnology platforms to deliver drugs to tumors. However, progress in developing effective drugs using this approach has been hampered by heterogeneity of EPR effect in different tumors and limited experimental data from patients on effectiveness of this mechanism as related to enhanced drug accumulation. This report summarizes the workshop discussions on key issues of the EPR effect and major gaps that need to be addressed to effectively advance nanoparticle-based drug delivery.