The incidence of thyroid cancer is increasing, especially papillary thyroid carcinoma (PTC), making it currently the fastest-growing cancer among women. Reasons for this increase remain unclear, but several risk factors including radiation exposure and improved detection techniques have been suggested. Recently, the induction of chromosomal fragile site breakage was found to result in the formation of RET/PTC1 rearrangements, a common cause of PTC. Chromosomal fragile sites are regions of the genome with a high susceptibility to forming DNA breaks and are often associated with cancer. Exposure to a variety of external agents can induce fragile site breakage, which may account for some of the observed increase in PTC. This paper discusses the role of fragile site breakage in PTC development, external fragile site-inducing agents that may be potential risk factors for PTC, and how these factors are especially targeting women.