To provide a brief overview of MTX resistance and strategies to mitigate its aftereffects in cancer therapy, a literature-based search was conducted using keywords such as cancer pathology, MTX mechanism and resistance, S100A4, folate uptake, folate efflux, P-glycoprotein, beta-catenin and anticancer properties of Vitamins A, D, E and K. Investigations encompassing in vitro studies, in vivo studies and clinical trials were reviewed to identify the mechanisms of resistance induced by MTX and the potential benefits of coadministering fat-soluble vitamins with existing anticancer drugs. This evidence concerns the gene CTNNB1 and cancer.