Cell-cell and cell-matrix adhesion are critical processes for the formation and maintenance of tissue patterns during development, as well as control of invasion and metastasis of cancer cells. Although great strides have been made regarding our understanding of the processes that play a role in cell adhesion and cell movement, the precise mechanisms by which diverse signaling events regulate cell and tissue architecture are poorly understood. One group of cell surface molecules, Eph receptor tyrosine kinases, and their membrane-bound ligands, ephrins, are key regulators in these processes. It is the ability of Eph/ephrin signaling pathways to regulate cell-cell adhesion and motility that establishes this family as a formidable system for regulating tissue separation and morphogenesis. Moreover, the de-regulation of this signaling system is linked to the promotion of more aggressive and metastatic tumors in humans.