Thyroid hormones (THs) are essential for the regulation of several metabolic processes and the energy consumption of the organism. Their action is exerted primarily through interaction with nuclear receptors controlling the transcription of thyroid hormone-responsive genes. Proper regulation of TH levels in different tissues is extremely important for the equilibrium between normal cellular proliferation and differentiation. The iodothyronine deiodinases types 1, 2 and 3 are key enzymes that perform activation and inactivation of THs, thus controlling TH homeostasis in a cell-specific manner. As THs seem to exert their effects in all hallmarks of the neoplastic process, dysregulation of deiodinases in the tumoral context can be critical to the neoplastic development. Here, we aim at reviewing the deiodinases expression in different neoplasias and exploit the mechanisms by which they play an essential role in human carcinogenesis. TH modulation by deiodinases and other classical pathways may represent important targets with the potential to oppose the neoplastic process.