Although patients diagnosed with axillary node-negative estrogen receptor-positive breast cancer have an excellent prognosis, about 15% of them fail after 5 years of tamoxifen treatment. Clinical trials have provided evidence that there is a significant benefit from chemotherapy for these patients, but it would be significant overtreatment if all of them were treated with chemotherapy. Therefore, context-specific prognostic assays that can identify those who need chemotherapy in addition to tamoxifen, or those who are essentially cured by tamoxifen alone, and can be performed using routinely processed tumor biopsy tissue would be clinically useful. Using a stepwise approach of going through independent model-building and validation sets, a 21-gene recurrence score (RS), based on monitoring of mRNA expression levels of 16 cancer-related genes in relation to five reference genes, has been developed. The RS identified approximately 50% of the patients who had excellent prognosis after tamoxifen alone. Subsequent study suggested that high-risk patients identified with the RS preferentially benefit from chemotherapy. Ideally the RS should be used as a continuous variable. A prospective study-the Trial Assigning Individualized Options for Treatment (Rx) (TAILORx)-to examine whether chemotherapy is required for the intermediate-risk group defined by the RS is accruing in North America.