Chemokines were recognized originally for their ability to dictate the migration and activation of leukocytes. However, CXC chemokine ligand 12 (CXCL12, also known as stromal cell-derived factor-1) and its receptor CXCR4 are the first chemokine and receptor that have been shown to be critical for developmental processes, including homing and maintenance of hematopoietic stem cells (HSCs), production of immune cells, homing of primordial germ cells (PGCs), cardiogenesis, arterial vessel branching in some organs, and appropriate assemblies of particular types of neurons. This review focuses on the pathophysiological relevance of CXCL12-CXCR4 signaling in mammals.