One of the most important considerations for patients undergoing radiotherapy is treatment related toxicity. Increased toxicity may lead to worse outcome as the delay of overall treatment time may adversely affect certain rapidly proliferating tumors. Acute and late toxicity can also affect patients' quality of life and healthcare economics. Various factors associated with increased radiotherapy related toxicity have been reported but controversy still exists. Radiotherapy given to patients with bilateral retinoblastoma as well as genetic factors such as neurofibromatosis and p53 mutation can lead to a higher rate of secondary carcinogenesis. Presence of BRCA 1 and 2, which are involved in DNA repair, were initially thought to have increased acute and late toxicity in the treatment of breast cancer, but more recent data have not shown this. Collagen vascular diseases such as systemic lupus erythematosus, scleroderma, mixed connective tissue disease have been associated with worse side effects and cosmesis with whole breast irradiation but less toxicity with partial breast irradiation. . The presence of co-morbid and chronic diseases such as diabetes, inflammatory bowel disease, COPD and obesity may also influence side effects and complications. This session will look at four different subgroups of patients with cancer (breast, thoracic, pelvic and pediatric) and examine which factors have been shown to adversely affect toxicity and what current information is available. Reasonable recommendation for management guidelines for the patients at risk for radiation-related toxicities will be discussed. At the conclusion of this activity, the learner will be able to do the following: 1. Identify which patients may have a higher rate of acute and late toxicity based on genetic predisposition, chronic illness or associated comorbidity. 2. Elucidate the mechanisms of radiation related toxicity in patients with certain genetic conditions, chronic illness and collagen vascular disease. 3. Summarize reasonable management guidelines for these challenging patients.