Thyroid hormone (TH) influences a wide variety of biological events in vertebrates. Among them, the balance between proliferation and differentiation is crucial in TH action in normal and pathological conditions, including cancer. Thyroid hormone signaling results from the interaction of T3 with nuclear receptors that, in concert with other transcription factors, stimulate or repress the expression of target genes, some of which are involved in the control of cellular proliferation. Ligand (T3) availability is under tight control at both extracellular and intracellular levels. Intracellular T3 concentrations are influenced by the action of selenodeiodinases. These enzymes can, within the single cell, enhance (D1 and D2) or reduce (D3) T3 concentrations, thereby constituting a potent mechanism of pre-receptoral control of TH action. Type 3 deiodinase, the major physiological inactivator of TH, is highly expressed in developing tissues and in some tumoral tissues, with a mostly unknown function. Recent studies suggest that D3 enzyme plays an important role in the control of TH metabolism and action during tumorigenesis. In this review, we focus on D3 and its potential as a novel tumoral marker and new molecular target in cancer treatment.