Chemokines are named and best known for their chemotactic cytokine activity in the hematopoietic system; however, their importance extends far beyond leukocytes, cell movement and immunoregulation. CXCL12, the most protean of chemokines, regulates development in multiple systems, including the hematopoietic, cardiovascular and nervous systems, and regulates diverse cell functions, including differentiation, distribution, activation, immune synapse formation, effector function, proliferation and survival in the immune system alone. The broad importance of CXCL12 is revealed by the complex lethal developmental phenotypes in mice lacking either Cxcl12 or either one of its two known 7-transmembrane domain receptors Cxcr4 and Ackr3, as well as by gain-of-function mutations in human CXCR4, which cause WHIM syndrome, a multisystem and combined immunodeficiency disease and the only Mendelian condition caused by a chemokine system mutation. In addition, wild type CXCR4 is important in the pathogenesis of HIV/AIDS and cancer. Thus, CXCL12 and its receptors CXCR4 and ACKR3 provide extraordinary examples of multisystem multitasking in the chemokine system in both health and disease.