The gastrointestinal (GI) tract handles a complex task of nutrient absorption and excretion of excess fluid, electrolytes, and toxic substances. GI epithelium is under constant proliferation and renewal. Differentiation of colonocytes occurs as they migrate from the basal layer to the apex of the crypt. Cells of the basal layer are highly proliferative but less differentiated, whereas apical cells are highly differentiated but non-proliferative. Alterations of this intricate process lead to abnormal proliferation and differentiation of colorectal mucosa leading to development of polyps and neoplasia. The effects of calcium (Ca) on colorectal mucosal growth have been extensively studied after the discovery of the calcium sensing receptor (CaSR). Fluctuation in extracellular Ca can induce hyperproliferation or quiescence. Disruption in the function of CaSR and/or changes in the level of CaSR expression can cause loss of growth suppressing effects of extracellular Ca. This review addresses the role of Ca and CaSR in the physiology and pathophysiology of colonocyte proliferation.