Head and neck squamous cell carcinoma (HNSCC) is a complex clinical entity, and its treatment strategy remains a challenge. The best practice management for individual HNSCC patients should be discussed within a multidisciplinary team. In the locally advanced disease, radiation therapy (RT) with or without concomitant cisplatin-based chemotherapy is the current standard of care for most patients treated definitively or adjuvantly after surgery. Intensity-modulated photon therapy (IMRT) is the recommended RT technique due to its ability to offer considerable treatment conformality while sparing surrounding normal critical tissues. At present, the development of novel treatment strategies, as well as alternative systemic agent combinations, is an urgent need to improve the therapeutic ratio in HNSCC patients. Despite the immune landscape suggesting a strong rationale for the use of immunotherapy agents in HNSCC, evidence-based data demonstrate that combining RT with immune checkpoint inhibitors as the primary treatment modality has not been shown to induce significant benefit on survival clinical outcomes. The objective of this article is to review the current literature on the treatment of patients with HNSCC. We initially provided a comprehensive overview of the standard of care. We then focused on the integration of systemic therapies with RT, highlighting the latest published evidence and ongoing trials which investigate different combination strategies in the definitive setting. Our hope is to summarize relevant literature in order to provide a foundation for interpreting emerging data and designing future trials to maximize care, both in disease control and patient quality of life.