The transcriptional control of blood stem cells is critical for their normal function, and a large number of leukaemias arise, when this fine balance of gene activities is disturbed. Transcription factors generally function as components of wider regulatory networks. Our group uses a combination of experimental and computational approaches to study transcriptional regulatory networks in blood stem cells; to discover how transcription factor networks control the function of blood stem cells; and to identify how perturbations of such networks can cause leukaemia. We are addressing these issues using computational analysis coupled with single cell gene expression studies, genome-scale analysis of transcription factor binding sites, and transgenic mouse assays. During my talk, I will provide an overview of the nature of our new data, and outline how they raise several fundamental questions concerning the functionality of transcription factor binding events and the dynamic nature of cross-regulatory relationships in both normal and malignant cells.