Cell growth is influenced by environmental stress. The mammalian target of rapamycin (mTOR), the central regulator of cell growth, can be either positively or negatively regulated by different stresses. The p38 MAP kinase pathway is a stress response pathway that can be activated by a variety of stresses, and one of the p38 group members, p38b, can inhibit or promote mTOR activation when cells are under different kinds of stress. We found that a cascade of p38b MAPK and p38 regulated/activated kinase (PRAK or MK5) participates in energy starvation-induced suppression of mTOR complex1 (mTORC1), that energy starvation activates the p38b-PRAK cascade, and that p38b- or PRAK-deletion diminishes energy depletion-induced suppression of mTORC1 and reduction of cell size. We show that PRAK directly regulates Ras homolog enriched in brain (Rheb), a key component of the mTORC1 pathway, by phosphorylation. The phosphorylation of Rheb at serine 130 by PRAK impairs Rheb’s nucleotide-binding ability and inhibits Rheb-mediated mTORC1 activation. Thus, the p38b-PRAK cascade targets Rheb to inhibit mTORC1 activity upon glucose depletion. In another stress situation in which cells are treated with arsenite, p38b was found to be involved in arsenite-induced activation of mTORC1. Arsenite-mediated oxidative stress activates p38b and induces interaction between p38b and Raptor, a regulatory component of mTORC1, resulting in the phosphorylation of Raptor on Ser863 and Ser771. The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation. Our results demonstrate that the p38 pathway can regulate different components of the mTORC1 pathway, and that p38b can target different substrates to either positively or negatively regulate mTORC1 activation when a cell encounters different environmental stresses.