Epigenetic mechanisms,including DNA methylation,are responsible for determining and maintaining cell fate,stably differentiating the various tissues in our bodies.Increasing evidence shows that DNA methylation plays a significant role in cancer,from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis.Recent studies also suggest a role for DNA methylation in drug resistance.This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance,with a focus on breast cancer.In addition,we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance.Hormone ablation is the therapy of choice for hormone-sensitive breast tumors,yet as many as 40％ of patients inevitably relapse,and these hormone refractory tumors often have a poor prognosis.Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment.Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells.Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood,and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts.Going forward,DNA methylome profiling will become increasingly central to epigenetic research,heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.