Intrinsic radioresistance of cancer cells remains a fundamental barrier to obtain the maximal efficacy of radiotherapy (RT) for the treatment of HNSCC. This resistance to RT is due, in large part, to aberrant inhibition of apoptosis in tumor cells. A number of signaling proteins and pathways that contribute to cellular survival are known to be overexpressed and/or hyperactivated in HNSCC. Among these, some members of the Blc-2 protein family, such as Bcl-2 and Bcl-XL, contribute this resistance by inhibiting the intrinsic mitochondrial pathway. ABT-737 is a rationally designed small molecule that binds with high affinity to Bcl-2 and Bcl-XL and antagonizes their anti-apoptotic function, thereby inducing apoptosis in many cancer cell types. Although ABT-737 has been shown to make HNSCC cells more susceptible to conventional chemotherapy, no prior study investigating the effect of ABT-737 in combination with radiotherapy has been undertaken for the treatment of HNSCC.