A great interest in the scientific community is focused on the improvement of the cure rate in patients with bone malignancies that have a poor response to the first line of therapies. Novel treatments currently include epigenetic compounds or molecules targeting epigenetic-sensitive pathways. Here, we offer an exhaustive review of such agents in these clinical settings. Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102 (Olutasidenib), inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 (Tazemetostat) To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of Phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers.