Off target toxicities is one of the hallmarks of conventional chemotherapy as only a tiny percentage of the injected dose actually reaches the tumor(s). Numerous strategies have been employed in attempts to achieve targeted therapeutic delivery to tumors. One strategy that has received immense attention has been the packaging of these chemotherapeutics into nanoparticles and relying on the enhanced permeation and retention (EPR) effect for targeting. However, few, if any, nanoformulations have been used clinically that actually show enhanced drug delivery to tumors. There are a number of biological barriers to successful targeted delivery and nanoparticles large enough to theoretically benefit from the EPR effect predominantly accumulate in the liver and spleen after systemic administration. Nanoparticles that do reach the tumor will experience challenges such as difficulty penetrating deeply into tumors and rapid uptake by macrophages rather than tumor cells. In order to overcome this, researchers are investigating a new drug delivery system by utilizing T-cells, macrophages, or stem cells (Mesenchymal/Neural Stem Cells) and loading them with therapeutic nanoparticles for targeted delivery due to either their organotropic or tumor tropic migratory capabilities. By exploiting the migration and motility of these particular cells, researchers have delivered drug-loaded nanoparticles as well as nanoparticles for use in thermal ablation and magnetic field treatments, with the goals of decreasing off-target toxicities and increasing intratumoral distribution of the therapeutic payload. This is an inherently complex drug delivery system that requires optimization of multiple parameters – including cell type, payload, cell loading, release rate from nanoparticle and more – for success. Here we review recent advances and upcoming challenges for the field.