Geno-phenotypic patterns of pre-invasive and invasive lobular breast cancers and infiltrating ductal carcinomas of low, intermediate, and high grade are reviewed. One of the main differences between lobular breast cancers and ductal carcinomas is the presence of inactivating E-cadherin gene mutations in lobular breast cancers. In many other respects, lobular breast cancers and low-grade ductal carcinomas exhibit similar geno-phenotypic profiles. The development of p53 dysfunction may be a hallmark of infiltrating ductal cancers of intermediate and high grade. Sequential Her-2/neu and ras abnormalities define a subset of aggressive high-grade tumors, and the development of Rb dysfunction may define a separate subset of aggressive ductal cancers. Based on these observations, a branching molecular evolutionary model for the development and progression of breast cancer is proposed.