Background & Aims: Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. Methods: Immunohistochemistry of FXR in normal (n=238), polyps (n=32), and adenocarcinomas, staged I-IV (n= 43, 39, 68, and 9), of the colon and RT-PCR, reverse phase protein array (RPPA) and western blot analysis in 15 colon cancer cell lines, NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas (TCGA), DNA methyltransferase inhibition, methyl-DNA immunoprecipitation (MeDIP), bisulfite sequencing and KRAS knock-down assessed were used to investigate FXR regulation in colon cancer development. Results: IHC and RT-qPCR revealed the expression and function of FXR was reduced in precancerous lesions and silenced in majority of stage I-IV tumors. FXR expression negatively correlated with PI3-kinase signaling and the epithelial-to-mesenchymal transition (EMT). The NR1H4 promoter is methylated in ~12% colon cancer TCGA samples, and methylation patterns segregate with tumor sub-types. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. Conclusion: FXR expression is decreased early in human colon cancer progression and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses EMT and other oncogenic signaling cascades and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.