The ability to predict the biological behavior of breast tumors can allow selection of the optimum treatment and follow-up strategies. Conventionally, tumor size, lymph node metastases, and histopathologic features have been used to determine the risk of systemic relapse. The discovery of a number of specific genetic and biochemical alterations in breast tumors has led to the molecular era of prognostic factors. Many of these molecular changes are determinants of relevant biological characteristics of malignancy, ie, dyregulated proliferation, invasion, and metastases. Preliminary data suggest that they may provide a better determination of the risk of relapse than can be ascertained by conventional prognostic factors alone. For example, amplification/overexpression of HER-2/neu oncogene has been shown to be a marker of increased risk of relapse after locoregional therapy of breast cancer. More recent studies have shown that it may also play a role in determining sensitivity to chemo-therapeutic drugs. It is expected that a greater understanding of the molecular basis of breast cancer growth regulation will allow a better identification of subjects who should receive systemic therapy and will also allow a better selection of the appropriate systemic therapy regimen.