SDF-1 is ubiquitously expressed in vertebrate tissues in a constitutive manner. It performs an essential role in cell migration and proliferation as well as participates in tissue-specific physiological processes such as neuromodulation. It is also involved in many pathological processes including: HIV infection, metastatic malignancy, chronic inflammatory disorders and benign proliferative diseases. SDF-1 is mostly regulated at the splicing, and not transcriptional level. Different splicing variants share agonist potency to their cognate receptor, CXCR4, but are characterized by distinct properties. SDF-1alpha is the predominant isoform found in all organs, but undergoes rapid proteolysis in blood. SDF-1beta is more resistant to blood-dependent degradation, stimulates angiogenesis and is present in highly vascularized organs such as: the liver, spleen and kidneys. In contrast, SDF-1gamma is located in very active, less vascularized organs susceptible to infarction such as the heart and the brain. The understanding of the functional diversity of the different splicing variants will help in developing therapeutic strategies.