Clustering breast cancers by their transcriptome into ‘molecular subtypes’ identifies a number of groups with unique biology, histopathology and clinical behaviour. The patterns of gene expression that distinguish these subtypes are the product of a gene expression regulatory network defined by multiple regulatory mechanisms including transcription factors, epigenetic modifications and RNA regulatory molecules such as microRNAs. We are interrogating a number of transcriptional and microRNA networks to identify novel biomarkers and therapeutic targets in breast cancer, with a focus on Estrogen Receptor-negative disease. In this presentation, I will describe unpublished evidence that the Inhibitor of Differentiation (Id) family of transcriptional regulators control not only mammary development and differentiation but are also critical controllers of malignancy and therapeutic responsiveness in a subset of ER-negative breast cancers.