Radiation therapy plays a critical role in the management of a majority of patients diagnosed with cancer. Identification of factors that help predict which patients are at risk for relapse within the irradiated field remains an active area of investigation. Although conventional clinical and pathologic factors have been helpful in identifying risk and guiding clinical decision-making for both local and systemic management, there is clearly a need to identify additional prognostic markers, which can aid in refining our treatment strategies and improving outcomes. A substantial amount of research efforts have been devoted to identifying molecular markers for prognostic and therapeutic strategies. The recent emergence of a powerful armamentarium of molecular tools has resulted in rapid expansion of our fund of knowledge and understanding of the molecular biology underlying tumor behavior and response. While a majority of these efforts have been focused on risk factors for metastatic disease and survival, there is a rapidly growing body of literature focused on molecular factors associated with radiation resistance and locoregional failure. In this review, we summarize recent advances and the available literature evaluating molecular markers as they relate to radiation sensitivity of solid tumors. Literature regarding the potential application of expression of genes related to apoptosis, angiogenesis, cell cycle, DNA repair and growth factors will be reviewed. Some of the basic biology and laboratory evidence demonstrating how the marker relates to radiation response and available correlative clinical studies employing these markers as prognostic tools are presented. The majority of molecular markers that have potential clinical significance with respect to radiation sensitivity and local control will be highlighted.