Among the various types of dietary agents, isothiocyanates (ITCs) have raised the scientific interest with their unique properties, against disease development, including modulation of the epigenetic machinery. In the context of malignant melanoma, our research efforts have aimed to understand how ITCs induce cell death by interacting with the epigenetic machinery and thus leading to inhibition of tumour growth. For this purpose, we have utilised an experimental in vitro model of human malignant melanoma consisting of normal keratinocytes as well as primary and metastatic melanoma cell lines. In this model, specific ITCs [e.g. Sulforaphane (SFN), Iberin (IBN), Allyl Isothiocyanate (AITC), Benzyl Isothiocyanate (BITC) and Phenethyl Isothiocyanate (PEITC)] were examined for their ability to influence specific histone acetylation and methylation marks, as a potential epigenetic therapeutic strategy against melanoma. Overall, we report that all ITCs inhibited melanoma cell proliferation and influenced acetylation and methylation status of specific lysine residues on H3 and H4 by modulating the expression of various histone acetyl transferases (HATs), histone deacetylases (HDACs) and histone methyl transferases (HMTs), in malignant melanoma cells. Our data highlight novel insights on SFN, IBN, AITC, BITC and PEITC interaction with components of the histone regulatory machinery, to exert their anticancer action in malignant melanoma.