Abstract: Fulvestrant is a selective estrogen receptor degrader (SERD), that can specifically bind to estrogen receptor (ER), block ER transcription activity, and induce the degradation of ER protein. However, along with its widespread use in breast cancer endocrine therapy, drug resistance does gradually develop. A better understanding of mechanisms on fulvestrant resistance and the exploration on precise targeted therapy is the key to breaking through treatment bottlenecks and subsequently improving the prognosis of patients. Here, we review research advances in the potential mechanisms of fulvestrant resistance and outline promising approaches such as combination therapy to overcome the resistance.