The strategic goal behind adjuvant therapy is to open novel avenues for colon cancer treatment by specifically inactivating pathways needed for the growth of tumor cells. 5-Fluorouracil (5-FU) therapy is a prominent conventional treatment for colon cancer that has been used for five decades. Among the rich diversity of chemotherapeutics, 5-FU has been extensively manipulated as an anticancer drug. The pharmacology of 5-FU has spawned myriad alternatives to achieve low-toxicity treatment for better colon cancer management. The existing highly toxic chemotherapeutic regimens, lack of new congeners with significant efficacy, and drug resistance to cancer cells have prompted scientists to manipulate conventional treatments. These factors make it imperative to rationalize the current 5-FU therapy in combination with synthetic or natural compounds by optimizing the dose with respect to pharmaco-kinetic and preclinical data. To attempt to tailor effective conventional 5-FU regimens, novel therapeutic perspectives associated with the 5-FU-based colon cancer chemotherapy currently available in clinical settings have been summarized. This review presents comprehensive summary of a dedicated literature search of databases (ie, PUBMED, CAPLUS, and MEDLINE) for adjuvant approaches such as NSAIDs (COX-II inhibitors), natural compounds, viral vectors, novel agents/molecules, and various targeted therapies, in combination with 5-FU in developing treatment alternatives for colon cancer.