Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex^,, through a class of silencing mediators termed SMRT or N-CoR,. Mutant forms of RARα, created by chromosomal translocations with either the PML (for promyelocytic leukaemia)^,, or the PLZF (for promyelocytic leukaemia zinc finger), locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML–RARα APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF–RARα patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.