The Eph receptors comprise the largest family of receptor tyrosine kinases (RTKs). The Eph receptors regulate cell-cell communication during development, and some of them are highly expressed in adult human epithelial cells. They play profound roles in diverse physiological processes, such as angiogenesis (formation of new blood vessels from pre-existing ones), bone morphogenesis, inflammatory host responses, neurodegenerative diseases, and cancer. The Eph receptors are unique among the RTKs, as their mechanism of activation is distinctly different and much more complex. Among the 14 Eph receptors, EphA2 is the one with the most profound links to cancer, and is associated with poor prognosis. Intriguingly, EphA2 overexpression in cancer is often accompanied by the loss of its ligands, suggesting that EphA2 behaves as an oncoprotein in the absence of ligand. Ligand binding and tyrosine phosphorylation, on the other hand, promote anti-tumorigenic activity. Thus, small peptide ligands that activate EphA2 could have utility in the clinic as anti-cancer drugs. Together with Elena Pasquale from the SBP Discovery Institute, we are characterizing the activity and the therapeutic potential of such peptides.