Estrogen receptor (ER) positive cancers represent the most common breast cancer subtype. While ER-directed therapies have tremendously improved the survival of women with ER-positive breast cancer, resistance to endocrine therapies occurs in a significant proportion of patients, through alternative/parallel signalling pathways, genomic or epigenetic mechanisms involving ER. A better understanding of these escape mechanisms to traditional ER-directed therapies have led to novel therapies being added to the armamentarium to treat ER-positive breast cancer. There is emerging data regarding regulation of ER genomic activity by other sex steroid receptors, which are commonly co-expressed with ER. These findings have led to the initiation of clinical trials through selective harnessing of sex steroid receptors to “push” ER towards anti-tumorigenic activity. This talk will focus on the biological rationale of novel therapeutic strategies for ER-positive breast cancer, and review the challenges faced translating these strategies into clinical trials.