Sorafenib is a small molecule, multi-kinase inhibitor used as an anti-cancer drug for treatment of Liver and Kidney cancers. It is reported to be in phase 2 clinical trials for colorectal cancer (CRC). This drug was reported to inhibit both surface associated and intracellular kinases such as Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), Fibroblast Growth Factor Receptor (FGFR), RAF, BRAF etc. This was shown to be effective against both mutant and wild type BRAF. There are some preliminary clinical reports of patients showing resistance to this drug on long-term usage. Our study aims at developing a resistant cell line model for the above drug and to understand the pathways and mechanisms involved in resistance development. Resistant model of HCT-116 cell line was developed by continuously culturing parental cell line in the presence of the drug. The IC50 values were compared between the parental cells and the cells exposed to drug continuously. BCL2 an anti-apoptotic protein was seen overexpressed in resistant cells in contrast to decreased expression in parental cells supporting the development of resistance.Further the multidrug resistance proteins MDR1 and ABCG-2 are highly up regulated in resistance model reconfirming the resistance development. This study aims at understanding how the JAK-STAT signaling pathway is modulated during drug resistance by expression profiling of molecules from this pathway by real time PCR. In this study, we found that JAK-STAT pathway is suppressed in the parental cells when treated with the sorafenib, but found actively expressed in resistant model. JAK-STAT signaling pathway is known to be activated in cancers and helps in regular proliferation of cancer cells. But as noticed from the above results upon drug treatment in parental cells this pathway get suppressed thereby leading to cell death. The active involvement of JAK-STAT pathway, which supports proliferation, was seen over expressed in drug resistance model.