Physicians treating breast cancer patients often wonder why this dreaded disease is still fatal in some women despite our best diagnostic and therapeutic efforts. Our own studies on prospectively documented cases spanning several decades have given us new insights for approaching this problem. By using imaging biomarkers to classify breast cancer subtypes according to their apparent site of origin, we found that a majority of breast cancer deaths (71%) occur in a minority of breast cancers (45%). Breast cancer deaths are significantly more likely to occur in women with multifocal acinar adenocarcinoma of the breast, AAB (13.1%), diffusely invasive breast cancers of ductal origin, DAB (24 %) and breast malignancies of mesenchymal hybrid cell origin, BCMO (33.7%) compared with women having unifocal invasive breast cancers (6.1%). Preventing more of these fatal events will require a re-evaluation of the current imperfect histopathologic terminology of breast cancer with special attention to the diffuse breast cancer subtypes, intensification of multimodality imaging and multidisciplinary management, as well as application of image guided large format histopathology.