Although much is understood about the ways in which transcription factors regulate various differentiation systems, and one of the hallmarks of many human cancers is a lack of cellular differentiation, relatively few reports have linked these two processes. Recent studies of acute myeloid leukaemia (AML), however, have indicated how disruption of transcription-factor function can disrupt normal cellular differentiation and lead to cancer. This model involves lineage-specific transcription factors, which are involved in normal haematopoietic differentiation. These factors are often targeted in AML — either by direct mutation or by interference from translocation proteins. Uncovering these underlying pathways will improve the diagnosis and treatment of AML, and provide a working model for other types of human cancer, including solid tumours.