Leukaemia stem cells (LSCs) are responsible for sustaining and propagating malignant disease, and, as such, are promising targets for therapy. Studies of human LSCs have served an important role in defining the major tenets of the cancer stem cell model, which centre on the frequencies of cancer stem cells, their potential hierarchical organisation and their degree of maturation. LSCs in acute myeloid leukaemia (AML) have recently been studied using mouse syngeneic models of leukaemia induced by MLL oncogenes. These studies have revealed that LSCs are more analogous to progenitor cells and employ embryonic stem cell-like genetic programmes for their maintenance, prompting a refinement of the original cancer stem cell model with important implications for design of therapies to selectively target LSCs.