Numerous studies have associated intake of sufficient amounts of calcium with reduced risk of colorectal cancer (CRC). The antiproliferative and prodifferentiating effects of calcium in colonocytes are suggested to be mediated, at least in part, by the extracellular calcium-sensing receptor (CaSR). In colorectal cancer (CRC), the expression of the CaSR is downregulated, thereby hindering the antitumorigenic effects of calcium. In this thesis, I aimed to determine the causes that lead to silencing of the CaSR expression in colorectal tumors. We investigated the following mechanisms as possible causes for loss of CaSR expression: DNA methylation, histone modifications, microRNAs, and transcriptional alterations. We measured the mRNA expression of the CaSR in 65 colorectal tumors and their adjacent mucosae from the same patients, and colon tumor cell lines by real time qRT-PCR. The CaSR protein levels were determined by immunofluorescence. We assessed the methylation levels of the CaSR promoter by pyro- and bisulfite-sequencing. We employed chromatin immunoprecipitation (ChIP) to determine the abundance of the transcription factor, glial cells missing 2 (GCM2), and the histone marks H3K4me2 and H3K9ac bound to the CaSR promoter. We studied the role of microRNAs on CaSR expression by transfecting colon cancer cell lines with respective microRNA mimics and inhibitors. To study the impact of transcriptional alterations on CaSR expression we treated colon cancer cell lines with 1,25-dihydroxyvitamin D3 (1,25-D3), interleukin 6 (IL6), and tumor necrosis factor alpha (TNF[alpha]). In this thesis, we found that silencing of the CaSR expression in colorectal cancer is dependent on aberrant epigenetic and transcriptional alterations. We showed that loss of CaSR expression in CRC was dependent on CaSR promoter 2 hypermethylation and H3K9 deacetylation. Additionally, we demonstrated that overexpression of miR-135b-5p and miR-146b-5p is associated with the loss of CaSR expression in colorectal tumors. Finally, we showed regulation of the CaSR expression by 1,25-D3 and proinflammatory cytokines in colon cancer cell lines.