SummaryMany melanoma cells are resistant to the anti‐proliferative effect of all trans retinoic acid (ATRA). Retinoic Acid Receptor‐β2 (RAR‐β2) mediates the ATRA growth inhibition. We found a correlation between the anti‐proliferative activity of ATRA and expression of RAR‐β2. There was not a strict correlation between DNA methylation of RAR‐β gene and its expression. There was no difference in global and RARβ specific nucleosome repeat length (NRL) in melanoma and melanocytes or between control and ATRA treated cells. Pan‐acetylation of H3 and H4 within the RAR‐β gene promoter was higher in cells expressing RAR‐β2. All trans retinoic acid treatment of responsive cells did not change pan‐acetylation of H3/H4, but addition of ATRA to non‐responsive cells increased H4 pan‐acetylation. Phytochemicals or the histone deacetylase inhibitor Trichostatin A did not restore expression of RAR‐β2. Treatment of WM1366 melanoma cells with 5‐aza 2′‐deoxycytidine reactivated RAR‐β2 gene expression and restored the ability of ATRA to further induce the expression of this gene. Therefore, promoter methylation is responsible for silencing of RAR‐β2 in some melanoma cells and pan‐acetylation of H3 likely plays a permissive role in expression of RAR‐β2.