There are a number of novel, biologically targeted therapies, including anti-epidermal growth factor receptor agents (eg, ZD1839 and C225 [cetuximab]), anti-angiogenic agents (eg, vascular endothelial growth factor receptor inhibitors endostatin and angiostatin), and vascular targeting agents (eg, ZD6126), currently undergoing clinical development for a range of human cancers. These agents generally have milder toxicity profiles than conventional cytotoxic agents, and have the potential to be combined effectively with radiotherapy and other conventional modalities in the treatment of malignancies. In this review we consider the mechanistic rationale for combining biologically targeted agents with radiotherapy, present preclinical data to validate this hypothesis, and discuss early clinical investigations of these novel combination therapies, with an emphasis on ongoing trials in non-small cell lung cancer.