Current investigations show that chemokine receptor CXCR4 is functionally expressed on a multitude of tissues and cell types, including different leukocyte subsets, hematopoietic progenitor cells and non-hematopoietic cells such as endothelial and epithelial cells. In 1996 CXCR4 was discovered as one of the co-factors required for supporting T-lymphocyte tropic HIV infection into permissive cells and, as a consequence, much attention has been paid to this receptor in terms of HIV pathophysiology. The sudden surge of interest and subsequent growth in CXCR4 research following this discovery has led to a number of surprising findings. As well as being important for lymphocyte trafficking and recruitment at sites of inflammation, it appears that CXCR4 and its ligand stromal cell-derived factor-1 play an important role in hematopoiesis and developmental processes such as organogenesis, vascularization and embryogenesis. These findings provide new insight into the activities of chemokine receptors on both hematopoietic and non-hematopoietic cells and indicate that these molecules have both a more widespread cellular expression pattern and a wider biological role than first envisaged.