Nanomaterials are developed for treating and diagnosing cancer, but only 0.7% (median) are delivered to a solid tumor. To address this delivery problem, we are examining each biological barrier to determine its impact on tumor delivery. Because the liver sequesters up to 70% of nanomaterials, in this study, we asked, if liver Kupffer cells were removed, what is the impact on tumor delivery? While we demonstrate that the tumor delivery increased up to 150 times, we achieved 2% for nanomaterials of different size, material, and tumor type. This suggests the need to focus on tumor pathophysiology to increase delivery efficiency, since this approach led to a greater availability of nanoparticles in the blood, but 98% did not accumulate in solid tumors.