ABSTRACT: Signal regulatory protein α (SIRPα), also known as cluster of differentiation (CD)172a or Src homology 2 domain-containing phosphatase substrate-1, is a cell surface receptor expressed on myeloid and hematopoietic stem cells and neurons. Accumulating data suggests an important role of SIRPα in cell signaling as a negative regulator of the phosphatidylinositol 3-kinase signaling and mitogen-activated protein kinase pathways. In various cancers, including prostate, breast and liver, as well as astrocytoma and myeloid malignancies, downregulation of SIRPα is frequently observed, resulting in activation of these downstream signaling pathways. In turn, cell proliferation, transformation, migration and invasion may occur. Recently, it has been reported that blocking CD47, an anti-phagocytic signal expressed on tumor cells and an SIRPα ligand, may serve as a promising therapeutic approach, particular for the treatment of acute myeloid leukemia. In the present review, the current findings on SIRPα are summarized, with particular focus on its role in cancer.