The calcium sensing receptor (CaSR) has played an important role as a target in the treatment of a variety of disease states over the last 20 plus years. In this review, we give an overview of the receptor at the cellular level and then provide details as to how this receptor has been targeted to modulate cellular ion transport mechanisms. As a member of the G protein-coupled receptors family, it has a high degree of homology with a variety of other members in this class, which could explain why this receptor has been identified in so many different tissues throughout the body. This diversity of locations throughout the body sets it apart from other members of the family, and may explain how the receptor interacts with so many different organ systems in the body to modulate the physiology and pathophysiology. The receptor is unique in that it has two large exofacial lobes that sit in the extracellular environment and sense changes in a wide variety of environmental cues including: salinity, pH, amino acids concentration, polyamines to name just a few. It is for this reason that there has been a great deal of research associated with normal receptor physiology over the last 20 years. With the ongoing research in more recent years a focus on the pathophysiology has emerged and the effects of receptor mutations on cellular and organ physiology. We hope that this review will enhance and update the knowledge about the importance of this receptor and stimulate future potential investigations focused around this receptor in cellular, organ, and systemic physiology and pathophysiology.