Radiotherapy plays an important role in the management of breast cancer. Whilst its role in achieving local control following surgery in patients with early stage cancer is well established, there is still unclear evidence to explain the factors governing radioresistance in patients who develop recurrences both in the breast and axilla. Radiotherapy induces damage to the DNA. Various cell cycle damage check points and DNA damage repair pathways have been demonstrated. Ataxia telangiectasia mutant (ATM) kinase, which is a member of phosphatidylinositol-3 kinase (PI-3K) family appears to play a central role in DNA damage check point pathways. Over-expression of Insulin like growth factor-I receptor (IGF-IR), Human Epidermal Growth factor receptors (HERS), Vascular Endothelial growth factor (VEGF) on the cell surface and increased concentration of Epidermal Growth factor in the extracellular fluid have been associated with radioresistance. Specific genes such as p53, BRCA, Bcl-2 and chromosomal characteristics like telomere lengths have also been identified as playing significant roles in radiation responsiveness of a cell. This article reviews the current data on general principles of radiotherapy, the cellular mechanisms that operate in response to radiation damage and various molecular markers, intranuclear and extranuclear which have been demonstrated to influence radiation sensitivity in breast cancer cells.