The chemokine superfamily consists of a large number of ligands and receptors. At first glance, this family appears redundant and their ligand-receptor relationships promiscuous, making its study challenging. However, analyzing this family from the evolutionary perspective greatly simplifies understanding both the organization and function of this apparently complex system. In particular, the functions of a subgroup of chemokines (designated homeostatic chemokines) have played pivotal roles in advancing our understanding of the organization and function of the cellular networks that shape the immune system. Here, we update the full scope of the human and mouse chemokine superfamilies and their relationships and summarize several important roles that homeostatic chemokines play in the immune system.