This article explores the sex difference in incidence and progression of differentiated thyroid cancer (DTC). The article examines epidemiologic studies highlighting sex disparities in survival rates between men and women, with women experiencing a more favorable prognosis before menopause. It also discusses the role of sex hormones, genetic and epigenetic factors, and the immune system as potential contributors to the underlying mechanism of sex difference in DTC. The article advocates for sex-specific research to better understand the molecular mechanisms behind these observed sex differences and to develop targeted, sex-specific, and more individualized therapies for advanced, radioactive iodine refractory thyroid cancer.