Thyroid cancer is the most frequently diagnosed endocrine cancer and causes more deaths than all other endocrine cancers combined. Research findings support the concept that a subpopulation of thyroid cancer cells displays properties characteristic of stem cells. These putative cancer-forming entities drive tumorigenesis as a result of their dual ability to undergo self-renewal and to differentiate into various types of cancer cells; they also mediate metastasis and are resistant to the effects of chemotherapy and radiation therapy. This Review discusses the cellular origin of thyroid cancer and the properties of the thyroid cancer stem cell niche. The article critically evaluates the methods used to identify molecular markers expressed by thyroid-cancer-initiating cells and outlines prospective therapeutic strategies to directly target these cells. Stem-cell technology offers an unprecedented opportunity to investigate these crucial cancer stem cell populations and to advance understanding of the molecular mechanisms that control disease processes. Such knowledge could potentially lead to the development of more effective and safer treatment regimens for late-stage thyroid cancer than are currently available.