The ER+/HER2+ subtype accounts for up to 10% of all breast cancers and is an important subtype as these cancers have a worse prognosis than ER+/HER2– breast cancers. While there is now considerable preclinical and clinical evidence that ER+/HER2+ cancers exhibit intrinsic and acquired resistance to endocrine therapy, it remains unclear what is driving this resistance to therapy. Clearly this is a pressing clinical issue as endocrine therapy remains at the forefront of systemic treatment for all women with ER+ disease. However, the majority of patients with ER+/HER2+ disease do respond well to endocrine therapy. The challenge, therefore, is in identifying, early in the process of treatment decision-making, who will respond to endocrine therapy and who might benefit from combined endocrine and HER2-targeted agents.