Histone deacetylases (HDACs) offer potentially attractive molecular targets for sensitizing cancers to treatment with radiation therapy. By affecting patterns of gene expression, differentiation, apoptosis, and enhanced responses to therapeutic agents may be induced in cancer cells. Here, we review the drug characteristics underlying design and screening of HDAC inhibitors with a focus on radiation-sensitizing properties. Radiation-sensitizing capacities have been observed in three model systems, squamous carcinoma of head and neck origin (SQ-20B), prostate adenocarcinoma (PC-3), and breast adenocarcinoma (MCF7). Cell-type specificities in radiation-sensitizing properties have been observed. Mechanisms underlying specificity are under investigation.