We present a global picture of the natural history of node-negative breast cancer in which two of three important biological processes have outstanding prognostic consequences. We propose that the transition from slow to fast proliferation of the tumor leads to the most dramatic aggravation of prognosis. Second, immune cell infiltration is of major importance to prevent disease progression in fast-proliferating breast carcinomas, regardless of estrogen receptor status. In the absence of endocrine treatment, steroid hormone receptor expression as a third axis is of limited prognostic importance. Dissecting tumors according to these three major biological axes will allow further understanding of biological processes relevant for tumor progression in patients with node-negative breast cancer.