Although Mg 2+ has a well-recognized role as an essential cofactor for all ATP-binding enzymes, its role as a signaling ion like Ca 2+ has been controversial. A requirement for Mg 2+ for optimal T lymphocyte stimulation was demonstrated more than 30 years ago, but the mechanism of its synergistic effect with Ca 2+ in T cell activation remains elusive. Here, we summarize our recent discovery of a signaling role for Mg 2+ in the T cell antigen receptor (TCR) signaling pathway from the study of a novel primary immunodeficiency now named X-linked immunodeficiency with Mg 2+ defect, EBV infection and neoplasia (XMEN). XMEN patients were found to have a deficiency in Magnesium Transporter 1 (MAGT1), a Mg 2+-specific transporter, which leads to the absence of a TCR-stimulated Mg 2+ flux and attenuation of T cell activation. We further showed that this Mg 2+ flux is required proximally for the temporal orchestration of phospholipase C-γ1 (PLCγ1) activation. Thus, our study not only provides a second messenger role for Mg 2+ to explain its synergism with calcium in T cell signaling, it also identifies a potential extracellular therapeutic target for T cell-specific immunomodulation.