Radiotherapy (RT), particularly when combined with chemotherapy, has progressively become the nonsurgical standard of care in the primary treatment of a variety of cancers. Likewise, hormonal therapy is routinely combined with RT for the treatment of hormone-sensitive tumors. In addition, the clinical efficacy of combining an epidermal growth factor receptor (EGFR) antagonist with RT was recently validated. In view of cancer heterogeneity and the availability of an increasing number of therapy options, identification of biomarkers that can predict tumor response to a given therapy is crucial in streamlining treatment and sparing patients from receiving often toxic and expensive therapies that are not likely to be effective. Well-established biomarkers for response to hormonal therapy and/or RT are tumor estrogen receptor and the receptor tyrosine kinase HER-2 for breast cancer and serum prostate-specific antigen for prostate carcinoma. Some markers of tumor hypoxia and the level of tumor EGFR expression have been shown to be independent predictors of tumor response to RT. The use of biomarkers for predicting tumor response to the combination of RT and chemotherapy has thus far been limited to the methylation status of O-6-methylguanine-DNA methyltransferase in patients with glioblastoma multiforme treated with the combination of RT plus temozolomide. No validated biomarkers for predicting the response to molecular therapeutics are currently available. In this review, we call for standardization and simplification of assay methods and stress the importance of conducting confirmatory prospective studies. Integrated plans for identifying molecular markers built into many ongoing trials will hopefully generate more insights in the near future.