BACKGROUND: Multigene assays performed on the primary tumors from women with non-metastatic breast cancer provide useful prognostic information and discriminate excellent versus poor outcome potential in diverse clinical scenarios. Recently, analyses were conducted to determine if these assays predict who benefits from adjuvant chemotherapy added to endocrine therapy and conversely, who might avoid chemotherapy because of lack of substantial benefit. This literature-based review summarizes these data and provides a perspective on the limitations and clinical utility of these assays. METHODS: The literature regarding multigene assays and signatures in early breast cancer was surveyed. Only two assays-- the 21-gene recurrence score (RS) assay (Oncotype DX) and the 70-gene signature (MammaPrint)--were analyzed in randomized or non-randomized clinical populations in order to determine the predictive utility of the test in the adjuvant chemotherapy setting in patients whose tumors were estrogen-receptor positive. These data are summarized by type of clinical analysis, with information on clinical utility and comparative studies with standard clinical-pathologic factors. RESULTS: From 2 independent analyses in phase III clinical trial settings with tamoxifen-alone control arms, the 21-gene RS assay defines a group of patients with low scores who do not appear to benefit from chemotherapy, and a second group with very high scores who derive major benefit from CMF or CAF chemotherapy. One study was conducted in node-negative disease, and the second in a node-positive population. Interaction terms were significant in both studies, and the effect of the assay remained upon adjustment for other standard factors. Utilizing a non-randomized clinical setting, the 70-gene signature could also predict chemotherapy benefit in the high risk group, versus no apparent benefit in the low risk group, an effect that remained after adjustment for standard factors. For both assays, the discordance rate between the assay prediction and clinical-pathologic risk category was approximately 30%. Clinical utility studies showed use of the assay results in a change in treatment decision in 25-30% of cases, most commonly from chemoendocrine therapy to endocrine therapy alone. SUMMARY: The prediction of adjuvant chemotherapy benefit over and above endocrine therapy using multigene assay-determined risk category differs greatly across risk level and challenges the previous adjuvant therapy paradigm that degree of benefit is the same regardless of risk. These data justify current clinical use of these assays, while ongoing prospective studies will refine their role in practice settings.