Carcinogenesis of the large bowel and rectum are generally considered to be part of the same disease and is termed colorectal cancer (CRC). Metastatic CRC (mCRC) is the third most common cancer and the second leading cause of cancer-related death for adults in the United States. In spite of therapeutic advancements in chemotherapeutic drugs and biological inhibitors, the 5-year survival rate for mCRC patients remains at 15%. Furthermore, certain patients do not respond robustly to current therapies and it is thought that this resistance is a result of differences in the tumor microenvironment (TME), more specifically, as a result of KRAS gene mutations. Viruses have distinct strategies that they use to overcome the sophisticated defense mechanisms of the infected host, and many have been identified as therapeutically viable oncolytic elements. One important member of therapeutically identified viruses is oncolytic reovirus (a naturally occurring, ubiquitous double-stranded (ds) RNA virus). Reovirus is naturally oncolytic with the ability to replicate in cells containing dysfunctional signaling cascades, including those with KRAS mutations, and is emerging as a potential therapy for KRAS mutant mCRC cells. Therapeutic intervention with reovirus has profound consequences on the host immune profile. It has been demonstrated that the gene expression profiles of the treated cells are altered. However, the modification of gene expression due to reovirus has been under-studied. This paper examines an in-depth modulation of gene expression over 15 days by transcriptome analysis. The potential interactions between gene significantly regulated genes are then discussed.