Rong Lu: In a recent issue of Nature, Philipp S. Hoppe and colleagues present their work on how blood-forming cells, called hematopoietic progenitors, commit to becoming particular blood cell types. Previously, scientists thought that these choices were determined by random changes in the levels of gene regulatory proteins called transcription factors that are linked to programming different blood cell fates. Through single cell live-imaging of cells in culture, the authors recorded the real-time activities of GATA1 and PU.1, transcription factors that were thought to initiate the decision choice between megakaryocytic-erythroid and granulocytic-monocytic lineages. Interestingly, the authors saw no evidence for fluctuating levels of the transcription factors in decision-making. Instead, the transcription factors appear to execute and/or reinforce lineage choices that have already been made. These intriguing findings challenge the current view and indicate further studies are necessary to identify the primary regulators determining lineage decision-making amongst blood cells.