The foundation for targeted therapy of cancers driven by members of the ErbB oncoprotein family was established initially by the demonstration that ectodomain binding monoclonal antibodies (mAb) could disable the protein kinase encoded by the HER2/neu oncogene. Homomeric and heteromeric erbB kinases play critical roles in the development of cancer and in the spread of early lesions. In particular, antibodies targeting the p185erbB2/neu receptor provide major clinical benefits in the treatment of breast cancer and also stomach cancer. As suggested by our study with oncogenic neu transgenic mice, anti-p185erbB2/neu antibodies are also effective in preventing the tissue hyperplasia that precedes tumorigenesis, tumor growth and the dissemination of ErbB2/neu kinase-positive cells into other tissues. As a therapeutic principle, “reversion of phenotype” for established tumors and “prevention” of tumorigenesis and spread can explain the basis for the benefits invoked by therapeutic and adjuvant therapies for breast cancer patients after cancers are surgically removed. These emerging principles being enlightened by ongoing studies of monoclonal antibody therapy will continue to provide guidance for the development of new targeted therapies for resistant tumors that arise after treatment.