Mammalian cells are prone to tumorigenesis when suffering the genotoxic stresses, and the existence of the tumor suppressors validly decrease this possibility. Gadd45α is one of the growth arrest and DNA damage-inducible (Gadd) 45 gene family members and serves as a stress sensor and tumor suppressor under most stress conditions, which is evidenced by cell cycle arrest, DNA repair, senescence or apoptosis triggered by induction of GADD45α expression. However, some recent reports have challenged this notion by demonstrating the correlation of GADD45α expression to cell survival and even progression of certain tumor cells. Therefore, GADD45?? seems to exert multiple roles in stress signaling and tumor development. Elucidation of the related mechanisms will be helpful for the establishment of novel tumor therapeutic strategy targeting GADD45α.