Mammalian cells are prone to tumorigenesis when suffering the genotoxic stresses, and the existence of the tumor suppressors validly decrease this possibility. Gadd45alpha 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 GADD45alpha expression. However, some recent reports have challenged this notion by demonstrating the correlation of GADD45alpha expression to cell survival and even progression of certain tumor cells. Therefore, GADD45alpha 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 GADD45alpha.