Pleiotrophin (PTN) is a potent mitogenic cytokine with a high affinity for the polysaccharide glycosaminoglycan (GAG). Although it is most strongly associated with neural development during embryogenesis and the neonatal period, its expression has also been linked to a plethora of other physiological events including cancer metastasis, angiogenesis, bone development, and inflammation. A considerable amount of research has been carried out to understand the mechanisms by which PTN regulates these events. In particular, PTN has now been shown to bind a diverse collection of receptors including many GAG-containing proteoglycans. These interactions lead to the activation of many intracellular kinases and, ultimately, activation and transformation of cells. Structural studies of PTN in complex with both GAG and domains from its non-proteoglycan receptors reveal a binding mechanism that relies on electrostatic interactions and points to PTN-induced receptor oligomerization as one of the possible ways PTN uses to control cellular functions.