The transcription factor PU.1 is an essential regulator of haemopoiesis and a suppressor of myeloid leukaemia. PU.1 displays a complex expression pattern characterized by high expression in myeloid cells and low amounts in lymphoid cells. Based on this transcriptional profile, and the analysis of cell lines and mice expressing altered levels of PU.1, a model has been proposed where the concentration of PU.1 determines cell fate, whereas the graded reduction, but not absence, of PU.1 facilitates leukaemogenesis. The recent reports of mouse strains that enable the accurate determination of PU.1 expression and the conditional inactivation of PU.1 in adult haemopoiesis have led us to re-examine our understanding of the complex functions of PU.1. Here, we will discuss the data that, we believe, argue against the dosage-sensitive model of PU.1-mediated lineage commitment and leukaemogenesis.