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The emerging molecular understanding of cancer cell behavior is leading to increasing possibilities to control unchecked cell growth and metastasis. On the other hand, development of multifunctional drug carriers at the ‘nano’-scale is providing exciting new therapeutic strategies in clinical management of cancer beyond the conventional cytotoxic drugs. A new frontier in this regard is the combinational use of complementary agents based on nucleic acids to overcome the limitations of conventional therapy. The existence of tightly-integrated cross-talk through multiple signaling and effector pathways have been appreciated for some time, and the plasticity of such a network to overcome one-dimensional intervention is stimulating development of combinational therapy. The objective of this review is to underline the cutting edge technologies and opportunities employed in combination cancer therapy using nucleic acids therapeutics for successful clinical translation. Here, we provide a detailed analysis of the multifunctional carriers designed for different types of payloads, surveying the biomaterials used to construct the functional carriers. We then provide effective nucleic acid combinations employed to obtain more comprehensive outcomes, highlighting the critical factors involved in successful therapy. We conclude with an authors’ perspective on the future of combinational therapy using nucleic acid therapeutics, articulating the main challenges to advance this promising approach to the clinical realm.