EGFR is a cell surface receptor that triggers cell growth and tumor progression, but recently, it has been found that EGFR can enter the nucleus and associates with transcriptional regulation, DNA replication, and DNA repair activities. Nuclear EGFR has also been shown to correlate with poor clinical outcome in breast, ovarian, esophagus, and oral cancers. We also recently identified several nuclear EGFR interacting proteins including RHA, a DNA binding protein, and the DNA replication licensing complex that are known to play a role in tumor progression. While it has also been shown that radiation-induced nuclear translocation of EGFR activates DNA dependent protein kinase (DNA-PK), which is involved in repair of irradiation induced double-strand DNA breaks, the mechanism remains elusive. EGFR may also associate with other nuclear partners to form complexes involved in cancer radioresistance. Our preliminary results demonstrate that nuclear EGFR forms a complex with DNA-PK and (human polynucleotide phosphorylase) hPNPase in response to γ-radiation. Together, we hypothesize that nuclear EGFR contributes to tumor progression.