Reversible acetylation is mediated by histone deacetylase (HDAC), which is involved in regulating a broad repertoire of physiological processes, many of which are under aberrant control in tumor cells. Inhibition of HDAC activity prompts tumor cells to enter apoptosis; therefore, the utility of HDAC inhibitors for the treatment of cancer has been investigated and several HDAC inhibitors have now entered clinical trials. Although the clinical picture is evolving and the precise clinical utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumor types have a favorable response to such agents. Hematological malignancies seem to be particularly sensitive, and vorinostat (also called suberoylanilide hydroxamic acid) has recently been approved for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease. There are considerable gaps in our understanding of how HDAC inhibitors exert their antitumor activity. In the absence of mechanistic insights into the apoptotic process or biomarkers that inform on responsive tumors, it is a challenge to predict tumor response to HDAC-inhibitor-based therapies with any degree of certainty. In this Review, we discuss recent developments in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and relate this information to the emerging clinical picture for the treatment of cutaneous T-cell lymphoma and related malignancies.