Endocrine therapy is a major treatment modality for hormone-dependent breast cancer. It has a relatively low morbidity, and there is evidence that antihormonal treatments have had a significant effect in reducing mortality for breast cancer. Despite this, resistance to endocrine therapy, either primary or acquired during treatment, occurs in the majority of patients, and is a major obstacle to optimal clinical management. There is therefore an urgent need to identify, on an individual basis, those tumors that are most likely to respond to endocrine therapy (so sparing patients with resistant tumors the needless side effects of ineffective therapy), and the mechanisms of resistance in tumors that are nonresponsive to treatment (so these can be bypassed). These needs are the focus of this review, which discusses the particular issues encountered when investigating the potential of multigene expression signatures as predictive factors for response to aromatase inhibitors, which have recently become front-line endocrine therapies for postmenopausal patients with breast cancer.