TRPM7 is a polypeptide with intrinsic ion channel and protein kinase domains whose targeted deletion causes cells to experience growth arrest within 24 hr and eventually die. Here, we show that while TRPM7's kinase domain is not essential for activation of its channel, a functional coupling exists such that structural alterations of the kinase domain alter the sensitivity of channel activation to Mg²⁺. Investigation of the relationship between Mg²⁺ and the cell biological role of TRPM7 revealed that TRPM7-deficient cells become Mg²⁺ deficient, that both the viability and proliferation of TRPM7-deficient cells are rescued by supplementation of extracellular Mg²⁺, and that the capacity of heterologously expressed TRPM7 mutants to complement TRPM7 deficiency correlates with their sensitivity to Mg²⁺. Overall, our results indicate that TRPM7 has a central role in Mg²⁺ homeostasis as a Mg²⁺ uptake pathway regulated through a functional coupling between its channel and kinase domains.