The heparin-binding polypeptide homologs pleiotrophin and midkine are the only known members of a family of secreted growth/differentiation cytokines. Pleiotrophin and midkine are both developmentally regulated and highly conserved among species. They signal a number of physiological functions involved with angiogenesis, neuorogenesis, cell migration, and mesoderm-epithelial interactions. Constitutive expression of pleiotrophin and midkine in responsive cells support their role as "tumor growth factors" and positive regulators of tumor angiogenesis. Widespread deregulation of pleiotrophin and midkine is found in many known human cancers or their derived cell lines, and the molecular targeting of pleiotrophin to block its signaling in tumor cells has limited tumor growth and metastasis in animal models. Elucidating the molecular mechanisms of pleiotrophin and midkine action in tumorgenesis and tumor angiogenesis may lead to the identification of novel targets for tumor therapy.