The c-myb proto-oncogene and its product (Myb) are key regulators of haemopoietic cell proliferation and differentiation. Myb mRNA is expressed at high levels in most human myeloid and acute lymphoid leukemias. Both normal and activated myb genes encode transcription factors (myb) which bind DNA in a sequence-specific manner and transactivate reporter genes containing appropriate Myb binding sites. Transformation by myb is likely to reflect increased transcription of some of the same genes that are normally regulated by c-myb. Myb can repress certain promoters and potential target genes that may be repressed by Myb have been identified. It has also been shown that several known co-repressors and at least one co-activator (CBP/p300) interact functionally with the Myb protein suggesting that transformation by Myb may be mediated by the coordinate activation of some target genes and repression of others. The interactions of various co-regulators was studied through a series of mutants whose ability to transform haemopoietic cells was tested. These studies provide new information on the mechanism of transformation and leukemogenesis by myb and support our hypothesis that binding of co-factors could be essential for the transforming potential of Myb. Identifying an interaction between Myb and a cofactor that is essential for Mybs transforming activity provides a target for drug screening and could widen the therapeutic window for inhibition of leukemic cell proliferation. These studies also contribute to our understanding of the process of leukaemogenesis in general, because transformation by myb can be viewed as a model or paradigm that is amenable to experimental analysis.