In colorectal cancer, BRAF and KRAS oncogenes are mutated in about 15% and 35% respectively at approximately the same stage of the adenoma-carcinoma sequence. Since these two mutations rarely coexist, further analysis to dissect their function of transformation in colon cancer is required. Caco-2 human colon adenocarcinoma cells were stably transfected with BRAF^V600E (Caco-BR cells) or KRAS^G12V (Caco-K cells) oncogenes. BRAF^V600E is more efficient in transforming Caco-2 cells and altering their morphology. The dominant nature of BRAF^V600E is evident by its ability to render Caco-2 cells tumorigenic in vivo all be it through selective extracellular signal-related kinase (ERK) 2 phosphorylation and high levels of cyclin D1. As a consequence, the cell cycle distribution of parental cells is altered and microsatellite instability is introduced. Attenuated ERK activation observed correlated with KSR downregulation by BRAF^V600E without further implications to signaling. Highly activated ERK in case of KRAS^G12V (Caco-K cells) leads to mild transformation causing Caco-K cells to express premature senescence-related markers and acquire growth factor-dependent viability. Interestingly, BRAF^WTgets equally activated by upstream KRAS mutations present in colon adenocarcinoma cells such as DLD-1 and SW620. Taken together, these results suggest that the two oncogenes have different transforming capability in colon cancer, although they both use the mitogen-activated protein (MAP) kinase pathway to carry out their effect. In general, BRAF^V600E presents greater potential in mediating tumorigenic effect as compared to KRAS^G12V both in vivo and in vitro. These findings may have implications in personalised diagnosis and targeted therapeutics.