New therapeutic interventions are essential for improved cancer management. Over the past decade, reovirus, a naturally-occurring oncolytic double-stranded RNA virus harboring an intrinsic preference to destroy mutant KRAS driven tumors, has shown novel promissory potential. The fact that more than 30-40% of human tumors harbor KRAS mutations had previously guided us to investigate the efficacy of reovirus in KRAS mutant colon cancer cells (CRC), and also to examine the cellular consequences of this biologic when used in combination with the chemotherapeutic drug, irinotecan, a Topoisomerase I inhibitor. Although much research is being undertaken to improve the drug efficacy by using in combination with other chemotherapeutic drugs, the plausible contribution of underlying signaling mechanisms which includes p21, a cyclin-dependent kinase inhibitor 1, in virus recognition and dissemination remains largely unexplored. This research highlight provides an insight into our current work to elucidate the precise role of p21 in favoring viral propagation in KRAS mutated CRC cells and in the process identify unique molecular players that can be effectively harnessed for improvement of the therapeutic efficacy of reovirus.