Myb was identified over four decades ago as the transforming component of acute leukemia viruses in chickens. Since then it has become increasingly apparent that dysregulated MYB activity characterizes many blood cancers, including acute myeloid leukemia, and that it represents the most “addictive” oncoprotein in many, if not all, such diseases. As a consequence of this tumor-specific dependency for MYB, it has become a major focus of efforts to develop specific antileukemia drugs. Much attention is being given to ways to interrupt the interaction between MYB and cooperating factors, in particular EP300/KAT3B and CBP/KAT3A. Aside from candidates identified through screening of small molecules, the most exciting prospect for novel drugs seems to be the design of peptide mimetics that interfere directly at the interface between MYB and its cofactors. Such peptides combine a high degree of target specificity with good efficacy including minimal effects on normal hematopoietic cells.