WHIM syndrome pathogenesis is causally linked to a variety of heterozygous gain-of-function (GOF) mutations in the C-terminus of the C-X-C chemokine receptor 4 (CXCR4), a master regulator of immune cell trafficking and homeostasis, causing desensitization defects, hyperactivation of downstream signaling (G-protein signaling, calcium mobilization, ERK/AKT activation), and retention of leukocytes in the bone marrow [3–11]. Here, CXCR4 is linked to WHIM syndrome.