For many decades, lung cancer has been the most common cancer and the leading cause of cancer death worldwide. More than 50% of non-small-cell lung cancer patients receive radiotherapy (alone or in combination with chemotherapy or surgery) during their treatment. The intrinsic radiosensitivity of tumors and dose-limiting toxicity restrict the curative potential of radiotherapy. Histone deacetylase inhibitors (HDACis) are an emerging class of agents that target histone deacetylase and represent promising radiosensitizers that affect various biological processes, such as cell growth, apoptosis, DNA repair, and terminal differentiation. Histone deacetylase inhibitors have been found to suppress many important DNA damage responses by downregulating proteins in the homologous recombination and nonhomologous end joining repair pathways in vitro. In this review, we describe the rationale for using HDACis as radiosensitizers and the clinical evidence regarding the use of HDACis for the treatment of non-small-cell lung cancer.