cAMP exerts differential effects on mitogenic signaling pathways. In many cells, cAMP inhibits growth factor-stimulated MAPK activity and proliferation. In others, cAMP promotes growth. TSH stimulates proliferation through elevations in cAMP in thyroid follicular cells. This mitogenic pathway is dependent upon both protein kinase A and Ras, but not upon Raf-1, mitogen-activated protein kinase kinase, or mitogen-activated protein kinase. We report that TSH, acting through cAMP, activates pp70s6k and that this activity is required for TSH-stimulated DNA synthesis. A similar role for pp70s6k in cAMP-mediated mitogenesis was observed in secondary rat Schwann cells and in Swiss3T3 fibroblasts, two additional cell types that respond to cAMP with growth. In contrast, cAMP elevation did not activate pp70s6k in NIH3T3 or REF52 fibroblasts, cells in which cAMP fails to stimulate proliferation. Together, these results suggest that pp70s6k plays an important and general role in cAMP-mediated proliferation.