Cyclin M (CNNM) constitute a family of proteins that function as Mg²⁺-extruding transporters by stimulating Na⁺/Mg²⁺ exchange, and thereby control intracellular Mg²⁺ levels. This CNNM-mediated Mg²⁺-extrusion is inhibited by the direct binding of phosphatase of regenerating liver (PRL), of which overexpression is frequently observed in malignant cancer tissues including colorectal cancer metastasis, and such inhibition is responsible for the malignant progression driven by PRL. Studies with CNNM knockout mice revealed the importance of CNNM4 and CNNM2 in maintaining organismal Mg²⁺ homeostasis by mediating intestinal Mg²⁺ absorption and renal reabsorption, respectively. Moreover, CNNM are known to be involved in various diseases; mutations in CNNM2 and CNNM4 cause dominant familial hypomagnesemia and Jalili syndrome, respectively, and genome wide association studies have also revealed the importance of CNNM2 in multiple major diseases including hypertension and schizophrenia. Collectively, the molecular and biological characterizations of CNNM family show that they are interesting therapeutic targets. The current status of drug development targeting these molecules is also discussed.