The development of nanoparticles (NPs) provides anticancer therapy with new strategies, such as noninvasive imaging and targeted drug delivery. However, uneven intratumoral distribution and immunogenicity hinder the clinical applications of NPs. Currently, mesenchymal stem cells (MSCs) are emerging as a hotspot in anticancer drug delivery due to their intrinsic characteristics, such as tumor-tropism and low immunogenicity. Herein, the combination of MSCs and NPs offers an advanced option to overcome the limitations of NPs. On the other hand, NPs could benefit MSC-based drug delivery systems in many aspects. Firstly, genetic modification is currently used in the design of cell vectors. More and more researchers prefer to use NPs to introduce exogenous genes into MSCs due to the lower risk of NPs compared with viral vectors. Secondly, as drug carriers, NPs could effectively protect MSCs from direct interaction with chemotherapy drugs and control the drug release profile of NPs–MSCs. Thirdly, some NPs exhibit a distinct promoting effect on the proliferation and migration of MSCs, which are beneficial to successful cell-based drug delivery. In the past few years, progress has been made in the combination of MSCs and NPs for treating cancer though the combined system is still in its infancy stage. Therefore, an overview of the current paradigm of the novel combined tumor-targeted drug delivery system is urgently demanded to provide valuable information for future clinical transformations of this combined drug delivery system.