The thyroid hormone receptors, encoded by the TRα and TRβ genes, are ligand-dependent transcription factors that belong to the nuclear receptor superfamily. In addition to the role of these receptors in growth, development and metabolism, there is increasing evidence that they also inhibit transformation and act as tumor suppressors. Aberrant TR action, as well as receptor silencing, are common events in human cancer, and TRs also have an important role in tumor progression in experimental animal models, suggesting that these receptors constitute a novel therapeutic target in cancer. This review highlights recent studies on mechanisms by which loss of expression and/or function of these receptors results in a selective advantage for cellular transformation, tumor development and metastatic growth.