In solid tumors, including non-small cell lung carcinomas (NSCLC) the existence of radioresistant subpopulations, such as quiescent or hypoxic tumor cells, is well established, thus posing a critical therapeutic problem. Although small-molecule inhibitors targeting cyclin-dependent kinases (CDK) were demonstrated to enhance cellular radiosensitivity preferentially in proliferating tumor cells, cell cycle-independent activities of these substances were recently suggested. In this study, the potential of a newer generation small-molecule CDK inhibitor, SNS-032, to sensitize radioresistant tumor cells to ionizing radiation was tested in vitro using two NSCLC cell lines (NCI-H460 and A549). Exposure of quiescent and hypoxic lung tumor cells to SNS-032 at a clinically achievable concentration (500 nM) prior to irradiation resulted in a significant increase in cellular radiosensitivity indicating cell cycle-unrelated mechanisms. The effect of SNS-032 on non-cycling cells was not attributed to an enhanced toxicity of the drug. A SNS-032 mediated delay in the resolution of radiation-induced gammaH2AX foci a surrogate for DNA double-strand breaks was determined in non-cycling cells, suggesting a modulation of DNA double-strand break repair. These results indicate a modulation of DNA double-strand break repair to be partially attributed to the radiosensitization effects of SNS-032 observed in hypoxic and quiescent lung tumor cells. Considering the importance of therapy resistance for the radiocurability of solid tumors, our findings may provide the basis for an improvement of the well-established treatment regimens in clinical oncology.