Histone deacetylas inhibitors (HDIs) are a novel prospective group of potential anti-cancer agents, some of them being tested in a clinical setting. The major mode of action of these compounds is inhibition of the cell cycle transition and, consequently, differential regulation of a number of genes necessary for cell proliferation, while favouring expression of genes rather associated with anti-proliferative pathways and with cell death signalling. This implies a possible role of HDIs in adjuvant treatment of tumours resistant to other agents, operating via a different molecular mechanism. The TNF-related apoptosis-inducing ligant (TRAIL) is a promising immunological inducer of apoptosis efficient against a variety of tumours with a remarkably selective mode of action. However, some malignancies are resistant to TRAIL treatment. In this paper, we review our current knowledge on HDI-mediated sensitisation of TRAIL-non-responsive tumours to this apoptogen and suggest a future clinical potential of HDIs and TRAIL in cancer management.