The EphA2 receptor tyrosine kinase is frequently overexpressed in many cancers, including 40% of breast cancers. Here, we show that EphA2 is a direct transcriptional target of the Ras-Raf-MAPK pathway and that ligand-stimulated EphA2 attenuates the growth factor-induced activation of Ras. Thus, a negative feedback loop is created that regulates Ras activity. Interestingly, the expression of EphA2 and ephrin-A1 is mutually exclusive in a panel of 28 breast cancer cell lines. We show that the MAPK pathway inhibits ephrin-A1 expression, and the ligand expression inhibits EphA2 levels contributing to the receptor-ligand reciprocal expression pattern in these cell lines. Our results suggest that an escape from the negative effects of this interaction may be important in the development of cancer.