Cancer is an extremely complex disease involving multiple signaling pathways that enable tumor cells to evade programmed cell death, thus making cancer treatment extremely challenging. The use of combination therapy involving both gene therapy and chemotherapy has resulted in enhanced anti-cancer effects and has become an increasingly important strategy in medicine. This review will cover important design parameters that are incorporated into delivery systems for the co-administration of drug and plasmid-based nucleic acids (pDNA and shRNA), with particular emphasis on polymers as delivery materials. The unique challenges faced by co-delivery systems and the strategies to overcome such barriers will be discussed. In addition, the advantages and disadvantages of combination therapy using separate carrier systems versus the use of a single carrier will be evaluated. Finally, future perspectives in the design of novel platforms for the combined delivery of drugs and genes will be presented.