Multidrug resistance (MDR) in tumors accounts for significant treatment failure. Particle carriers offer potential benefits for treating cancer, including the ability to target tumors and to deliver multiple cargo, providing opportunities to overcome drug resistance. In this Perspective, we provide a brief introduction to the MDR mechanisms and implications of tumor heterogeneity that contribute to drug resistance. We also highlight recent advances in the design of particles aimed at treating resistant tumors through particle-based codelivery of therapeutics. Finally, we discuss future directions, where an increased understanding of the tumor biology can be leveraged to develop new and improved particle-based cancer therapies.