The forkhead family of transcription factors is involved in tumorigenesis in rhabdomyosarcoma and acute leukemias. Within the family, three members (FKHR, AFX, AND FKHRL1) have sequence similarity to the nematode homolog Daf 16, recently shown to mediate signaling via a pathway involving IGFR1, P13-K and Akt. There are three potential Akt phosphorylation sites on the FKHR proteins. One site, FKHR Ser256 is found in the Forkhead domain and the other two are outside this domain. Recent studies show that phosphorylation of FKHR family members by Akt promotes cell survival. Phosphorylation regulates FKHR nuclear translocation and target gene transcription. Insulin also stimulates FKHR phosphorylation at Ser253.