Chemoradiation is the major treatment option in unresectable, locally advanced non-small cell lung cancer. Many clinical trials have evaluated the efficacy of different combinations of chemotherapy and radiotherapy in this heterogeneous patient population. Early clinical trials showed a survival advantage of sequential chemo-RT compared to radiation alone. Subsequent trials demonstrated that concurrent chemo-RT improved survival over sequential chemo-RT. More recent studies have suggested that there is no advantage to adding induction chemotherapy prior to concurrent chemo-RT, or to adding consolidation chemotherapy after concurrent chemo-RT. Various clinical trials have used different chemotherapy regimens, though there is still no consensus about those which are most effective. Additionally, different radiotherapeutic strategies have included hyperfractionation vs. standard fractionation, use of 3-dimensional techniques, and altering total radiation dose. As these methods are being perfected, much attention has turned toward the use of molecularly targeted therapies. This review summarizes recent clinical trials examining the role of chemo-RT in locally advanced non-small cell lung cancer and the movement toward personalized medicine.