How does breast cancer progress? There is evidence both to support (S. W. Duffy et al., Br. J. Cancer, 64: 1133-1138, 1991; R. Rajakariar et al., Br. J. Cancer, 71: 150-154, 1995) and refute (M. Hakama et al., Lancet, 345: 221-224, 1995; R. R. Millis et al., Eur. J. Cancer, 34: 548-553, 1998) the hypothesis of dedifferentiation; the theory that as breast cancers grow they evolve from well differentiated (grade I) to poorly differentiated (grade III) tumors. We provide evidence to support the view that the majority of grade I tumors do not progress to grade III tumors. Comparative genomic hybridization was used to screen entire genomes of a large sample (40 grade I and 50 grade III) of invasive ductal breast carcinomas, stratified by grade. We found distinct genetic differences between grade I and grade III tumors. Significantly, we found that 65% of grade I tumors lost the long arm of chromosome 16 compared with only 16% of grade III tumors. This pattern of loss leads us to conclude that the majority of grade I tumors do not progress to grade III tumors. These findings have important implications because they suggest that different breast tumor grades may have distinct molecular origins, pathogenesis, and behavior and, therefore, potentially present distinct molecular targets for research and treatment.