Signal regulatory protein alpha (SIRP alpha), also known as SHPS-1/BIT/ CD172a, is an immunoglobulin superfamily protein that binds to the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region. CD47, another immunoglobulin superfamily protein, is a ligand for SIRP alpha, with the two proteins constituting a cell-cell communication system (the CD47-SIRP alpha signalling system). SIRP alpha is particularly abundant in the myeloid-lineage hematopoietic cells such as macrophages or dendritic cells (DCs), whereas CD47 is expressed ubiquitously. Interaction of CD47 (on red blood cells) with SIRP alpha (on macrophages) is thought to prevent the phagocytosis by the latter cells of the former cells, determining the lifespan of red blood cells. Recent studies further indicate that this signalling system plays important roles in engraftment of hematopoietic stem cells as well as in tumour immune surveillance through regulation of the phagocytic activity of macrophages. In the immune system, the CD47-SIRP alpha interaction is also important for the development of a subset of CD11c(+)DCs as well as organization of secondary lymphoid organs. Finally, the CD47-SIRP alpha signalling system likely regulates bone homeostasis by osteoclast development. Newly emerged functions of the CD47-SIRP alpha signalling system thus provide multiple therapeutic strategies for cancer, autoimmune diseases and bone disorders.