Lung cancer (LC) is the leading cause of cancer related deaths and treatment with ionizing radiation (IR) and platinum based DNA damaging agents has had minimal advances. Additionally, patients suffer acute and chronic side-effects due to the high doses of IR that severely limit their quality of life. Therefore, new treatment methods are needed in combination with lower doses of radiation. The Rassool laboratory has recently shown that Poly (ADP-Ribose) Polymerase (PARP) and DNA methyltransferase (DNMT) interact, and inhibition of these proteins increased cytotoxicity in vitro and in vivo in breast, ovarian, and leukemia cancer models. We show here that treatment of LC tumors with both PARP and DNMT inhibitors is effective at reducing viability and clonogenicity, and reducing tumorigenicity in vivo. Moreover, combining the two inhibitors with low radiation doses further decreases tumor growth. This suggests that this therapy can potentially target tumors, while improving effects on normal tissues.