In the last decade the concepts of breast cancer dedifferentiation and progression have undergone a significant and substantial change. In the past it was widely believed that the detailed associations between genetic and morphological changes defined in the Vogelstein model of colorectal cancer pathogenesis could be transferred to breast carcinogenesis. A multitude of studies seemed to verify this a priori hypothesis. However, with the introduction of global screening techniques, predominantly at the DNA level, it became obvious that this linear model might be oversimplified for breast cancer. It is now widely accepted that losses of chromosomal 16q characterize in-situ and invasive breast cancer tumours with predominantly low tumour grade and estrogen receptor (ER) positivity (luminal breast cancers). In contrast, high grade breast cancers of the HER2, the basal or the non expressor phenotype with 16q-losses are rarely seen and in consequence a concept of multiple, parallel pathways with defined precursor lesions emerged. As a consequence, it became obvious that the hunt for oncogenes/tumour suppressor genes in invasive breast cancer is pathway specific. Whereas high grade breast cancers have been relatively well characterized by several recurrent changes in oncogenes/tumour suppressor genes located on various chromosomal regions (e.g. egfr, p53, HER2), the characterization of a 16q-specific tumour suppressor gene in ER-positive breast cancer is still a tremendous challenge. This review will focus on the role of 16q in breast cancer and aims to give insights into actual research efforts, e.g. alternative explanations in order to unravel the central role of 16q in breast cancer.