The Eya proteins were originally identified as essential transcriptional co-activators of the Six family of homeoproteins. Subsequently, the highly conserved C-terminal domains of the Eya proteins were discovered to act as a Mg2+-dependent Tyr phosphatases, making Eyas the first transcriptional activators to harbor intrinsic phosphatase activity. Only two direct targets of the Eya Tyr phosphatase have been identified: H2AX, whose dephosphorylation directs cells to the DNA repair instead of the apoptotic pathway upon DNA damage, and ERβ, whose dephosphorylation inhibits its anti-tumor transcriptional activity. The Eya Tyr phosphatase mediates breast cancer cell transformation, migration, invasion, as well as metastasis, through targets not yet identified. Intriguingly, the N-terminal domain of Eya contains a separate Ser/Thr phosphatase activity implicated in innate immunity and in regulating c-Myc stability. Given the role of Eya’s Tyr phosphatase in cancer, targeting this activity may be an attractive approach for cancer therapy.