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), an Mg(2+)-specific transporter, which leads to the absence of a TCR-stimulated Mg(2+)flux and an 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.