Identification of genes that modulate radiation sensitivity provides important tools to study cellular responses to ionizing radiation. We combined DNA microarrays and viability assays to identify modulators of radiation sensitivity in A549 lung cancer cells. Up-regulated genes were selected from microarray experiments and RNA expression levels were confirmed by real-time RT-PCR analysis. Cell viability assays such as clonogenic assay, MTT and FACS analysis of cell death, identified the ELAVL4 gene as a novel modulator of radiation sensitivity. ELAVL4 expression was induced following ionizing irradiation. Depletion of the ELAVL4 gene increased radiation sensitivity of A549 cells as shown by decreased surviving cell fraction following irradiation in clonogenic assay. Enhanced radiation sensitivity of ELAVL4-depleted cells was attributable to decreased cell proliferation as well as increased apoptotic cell death following irradiation. Thus the endogenous function of ELAVL4 in relation to radiation sensitivity might be the regulation of cell proliferation and death. This approach to identification of modulators for radiation sensitivity has several advantages in terms of functional selectivity, stringency and time. Further analysis of the modulators should find potential use in the application of radiation biomarkers as well as modulators of cellular radiation responses.