Histone deacetylase inhibitors (HDACIs) are epigenetically acting agents that modify chromatin structure and by extension, gene expression. However, they may influence the behavior and survival of transformed cells by diverse mechanisms, including promoting expression of death- or differentiation-inducing genes while downregulating the expression of prosurvival genes; acting directly to increase oxidative injury and DNA damage; acetylating and disrupting the function of multiple proteins, including DNA repair and chaperone proteins; and interfering with the function of corepressor complexes. Notably, HDACIs have been shown in preclinical studies to target transformed cells selectively, and these agents have been approved in the treatment of certain hematologic malignancies, for example, cutaneous T-cell lymphoma and peripheral T-cell lymphoma. However, attempts to extend the spectrum of HDACI activity to other malignancies, for example, solid tumors, have been challenging. This has led to the perception that HDACIs may have limited activity as single agents. Because of the pleiotropic actions of HDACIs, combinations with other antineoplastic drugs, particularly other targeted agents, represent a particularly promising avenue of investigation. It is likely that emerging insights into mechanism(s) of HDACI activity will allow optimization of this approach, and hopefully, will expand HDACI approvals to additional malignancies in the future.