Thyrotropin (TSH) is considered the main regulator of thyrocyte differentiation and proliferation. Thus, the characterization of the different signaling pathways triggered by TSH on these cells is of major interest in order to understand the mechanisms implicated in thyroid pathology. In this review we focus on the different signaling pathways involved in TSH-mediated proliferation and their role in thyroid transformation and tumorigenesis. TSH mitogenic activities are mediated largely by cAMP, which in turn may activate protein kinase (PKA)-dependent and independent processes. We analyze the effects of increased cAMP levels and PKA activity during cell cycle progression and the role of this signaling pathway in thyroid tumor initiation. Alternative pathways to PKA in the cAMP-mediated proliferation appear to involve the small GTPases Rap1 and Ras. We analyze the Ras effectors (PI3K, RalGDS and Raf) that are thought to mediate its oncogenic activity, as well as the ability of Ras to induce apoptosis in thyrocytes. Finally, we discuss the activation of the PLC/PKC cascade by TSH in thyroid cells and the role of this signaling pathway in the TSH-mediated proliferation and tumorigenesis.