Pleiotrophin (PTN) and midkine (MK) are members of a family of developmentally regulated, secreted heparin-binding proteins. The proteins are structural homologs, and are highly conserved among species. Although no homology has been detected with other heparin-binding growth factors, their functional similarity to members of the fibroblast growth factor (FGF) family is remarkable. PTN and MK are expressed during embryogenesis, showing an expression pattern that suggests functions in neurogenesis, cell migration, secondary organogenetic induction, and mesoderm-epithelial interaction. The widespread downregulation of PTN and MK in the adult human is reverted in a number of cancers, in which polypeptides are able to act as both transforming growth factors and promoters of angiogenesis. Elucidating the molecular mechanisms of PTN and MK action could lead not only to a deeper understanding of developmental processes, but also to the ultimate identification of targets for tumor therapy.