In the era of personalized oncology biomarkers that identify subgroups of specific cancers and help predict response to specific therapies are critical tools for prognosis determination and therapeutic decisions. The Estrogen Receptor (ER) had been one of the first biomarkers used in breast cancer and has helped advance the field of breast oncology by contributing to the success of hormonal therapies for the ER positive subgroup of the disease. Expression of the receptor in 1% or more of tumor cells in immunohistochemical sections define currently the ER positive subgroup of breast cancers, which may be treated with regimens that include hormonal inhibitors. The highest sensitivity and benefit of hormonal therapies is observed in cancers with robust ER expression (in 90% to 100% of tumor cells). However, it has become clear that the subgroup of breast cancers with low ER expression (in 1% to 10% of tumor cells) behaves similarly to ER negative breast cancers and has an inferior response to hormonal therapies. The behavior of the rest of ER positive breast cancers with an intermediate ER expression between these 2 extremes (ER expression between 10% and 90%) is less well described and their response to estrogen targeting therapies is less clear. Breast cancers with intermediate ER expression represent a small subgroup of ER positive breast cancers and the wide range of expressions suggests heterogeneity. This review will discuss this subgroup of ER positive breast cancers and examine their genomic landscape and therapeutic repercussions.