Concurrent chemoradiotherapy (cCRT) has improved outcomes and cancer cure rates in multiple malignancies and is used as the standard of care in neoadjuvant, primary (definitive), or adjuvant settings. Chemotherapy and targeted agents mostly increase the efficacy of radiation (RT). It has become the mainstay of treating locally advanced solid tumors aiding organ preservation, avoiding surgeries, and as an adjuvant treatment protocol. Chemotherapy agents with radiosensitizing properties (i.e., cisplatin, carboplatin, capecitabine, 5-fluorouracil, and taxanes) and several novel agents (e.g., epidermal growth factor receptor inhibitors (EGFR) and several other targeted therapies) have shown promising interactions with radiation. cCRT can be used with the intent of tackling distant metastasis, improving local control, and even survival by making cells more sensitive to radiation.