The dominant treatment paradigm for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) involves postoperative or definitive radiotherapy with concurrent cisplatin chemotherapy. Despite years of research investigating de-intensified treatment, cisplatin-based chemoradiotherapy remains the standard, yet it is associated with significant acute and chronic toxicity. However, due to shared risk factors, such as advanced age, and tobacco and alcohol use, patients with HNSCC frequently have comorbid illnesses that impact treatment tolerability, adding complexity to treatment-related decision-making. In addition, many patients have medical contraindications to cisplatin, requiring alternative treatment strategies. It is thus important to consider how well patients are likely to tolerate treatment, and how to adapt treatment in response to a patient's condition, when weighing treatment options. In this review, we aim to offer readers guidance in managing the elderly or comorbid patient with HNSCC, with particular attention to (i) approaching comorbidity and fragility assessment to make determinations on intensity of treatment, (ii) considering primary treatment modality (eg, surgery vs radiotherapy, chemo-radiotherapy vs radiotherapy alone) and (iii) choice of concurrent systemic therapy agent.