Recommendation of systemic adjuvant therapy and choice of optimal agents for early-stage breast cancer remains a challenge. Adjuvant therapy is indicated on the assumption of residual micrometastatic disease. Adjuvant assessment tools for prognosis and prediction of treatment benefit, including Adjuvant! Online, the St Gallen Consensus, Oncotype DX(®) and MammaPrint(®), aid clinical decision making. However, all of these tools have limitations that must be considered in their judicious application. Clinicopathological based tools are critically dependent on accurate, standardized measurement of parameters. Multigene tools are appealing for their objectivity and reproducibility, particularly regarding analysis of proliferation, but these approaches still overlook the biological heterogeneity within tumors evidenced by distinct cell subpopulations with different genomic patterns and function. The greatest treatment challenge remains for patients assessed as intermediate risk of relapse, a problem not overcome by multigene tools. Remarkable diversity in breast cancer dictates that adjuvant management must be biologically driven. Future identification of predictive biomarkers for specific chemotherapy sensitivity may allow targeted use of available agents, including anthracyclines, taxanes and DNA damaging agents. The presence of drug targets and targetable signaling pathways, rather than molecularly defined subgroups, may ultimately drive treatment decisions.