The chemokine SDF-1 (CXCL12) and its receptor CXCR4 are involved in regulation of migration, survival, and development of multiple cell types, including human hematopoietic CD34+/CD38-/low and stromal STRO-1+ stem cells. During steady-state homeostasis, CXCR4 is expressed by hematopoietic cells and also by stromal cells, which are the main source for SDF-1 in the bone marrow (BM). Stress-induced modulations in SDF-1 and CXCR4 levels participate in recruitment of immature and maturing leukocytes from the BM reservoir to damaged organs as part of host defense and repair mechanism. In addition, trafficking of SDF-1 is mediated by CXCR4, expressed by endothelial and various stromal cell types in the BM, spleen, and other organs, but not by hematopoietic cells. Transcytosis of functional SDF-1 to the BM takes place also in the stem cell-rich endothelium and endosteum regions, regulating hematopoietic and stromal interactions in the stem cell niche. Dynamic levels of SDF-1 and CXCR4 expression induce proliferation of hematopoietic and mesenchymal progenitors, recruitment of bone-resorbing osteoclasts, osteoblasts, neutrophils, and other myeloid cells, leading to leukocyte mobilization. These studies will be reviewed together with the mechanisms that regulate SDF-1 and CXCR4 physiologic function, inactivation, presentation, and availability. Moreover, the role and the dynamic modulations of this ligand and its receptor in alarm and pathologic conditions will be discussed as well.