Abstract: Approximately 70% of human breast tumors express hormone receptors (HRs), comprising the estrogen receptor (ER) and/or progesterone receptor (PR).The ER is the primary transcription factor driving oncogenesis in HR-positive (HR+) breast cancers; it is both a target of, and predictor of response to, antiestrogen therapy. Unlike in other breast cancer subtypes, more than half of all disease recurrences in HR+ breast cancer occur 6 years or more after diagnosis, particularly following 5 years of adjuvant anti-estrogen therapy. Late relapses in HR+ breast cancer thus represent a significant clinical challenge. There is considerable molecular and clinical heterogeneity underlying HR+ breast cancers, and a limited understanding of the mechanisms underlying treatment resistance and late relapse. In this review, we describe the long natural history of HR+ breast cancer and discuss relapse patterns in relation to their clinicopathological and molecular characteristics. We highlight the relationship between tumor relapse and anti-estrogen therapy resistance, and we describe the concept of tumor dormancy. Finally, we review novel translational research strategies utilizing preclinical models and patient tumor samples, and current clinical strategies that address this increasingly common challenge in breast cancer.