The activation of a T cell through T cell receptor (TCR) is fundamental to adaptive immune responses. The lymphocyte specific kinase (LCK) plays a central role in the initiation of signaling from the TCR. TCR activates LCK through the adaptor protein uncoordinated 119 (UNC119). A mutation of human UNC119 impairs LCK activation and is associated with inadequate signaling, diminished T cell responses to TCR stimulation, CD4 lymphopenia, and infections of viral, bacterial, and fungal origin. The above clinical and immunological findings meet the criteria of the idiopathic CD4 lymphopenia (ICL). The discovery of the UNC119 defect provides a molecular mechanism for a subset of patients with this previously unexplained disease. Here we review our recent findings on the UNC119 mutation in ICL.