Forced dimerization or oligomerization has emerged as a powerful mechanism for unleashing the oncogenic properties of chimeric transcription factors in acute leukemias. Fusion of transcriptional regulators with a variety of heterologous partner proteins as a consequence of chromosomal rearrangements induces inappropriate self-association, leading to aberrant transcriptional properties and leukemogenesis. Forced dimerization/oligomerization may alter the association of a DNA-binding protein for its transcriptional cofactors, or the dimerization motifs themselves may constitutively recruit transcriptional effector molecules. Oligomerized chimeras may also sequester essential partners or cofactors to exert dominant-negative effects on target gene expression. A key mechanistic feature, and one with major clinical implications, is the nature of the transcriptional cofactors that are recruited by the dimerized oncoprotein. Chimeric RARalpha and acute myeloid leukemia 1 (AML1) proteins induce constitutive repression after the recruitment of corepressors, whereas inappropriate maintenance of target gene expression by mixed-lineage leukemia (MLL) chimeras may result from the recruitment of coactivators or the basal transcriptional machinery. Molecular therapies directed at enzymatic activities of the aberrantly recruited cofactors, or antagonism of dimerization itself, represent promising avenues of current and future investigation.