Podocalyxin, a sialomucin most closely related to CD34 and endoglycan, is expressed by kidney podocytes, hematopoietic progenitors, vascular endothelia, and a subset of neurons; aberrant expression has recently been implicated in a range of cancers. Through interactions with several intracellular proteins and at least one extracellular ligand, podocalyxin regulates both adhesion and cell morphology. In the developing kidney, podocalyxin plays an essential role in the formation and maintenance of podocyte foot processes, and its absence results in perinatal lethality. Podocalyxin expression in the hematopoietic system correlates with cell migration and the seeding of new hematopoietic tissues. In addition, it is abnormally expressed in subsets of breast, prostate, liver, pancreatic, and kidney cancer as well as leukemia. Strikingly, it is often associated with the most aggressive cases, and it is likely involved in metastasis. Thus, a thorough investigation of the normal activities of podocalyxin may facilitate the development of new cancer treatment strategies.