For the past 2 decades, cisplatin-based adjuvant chemoradiotherapy (CRT) has remained the standard of care for patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) who are at high risk of disease recurrence. However, many patients are deemed ineligible for cisplatin-based CRT because of poor performance status, advanced biological age, poor renal function, or hearing loss. Because outcomes with radiotherapy (RT) alone remain poor, patients at high risk of disease recurrence deemed ineligible to receive cisplatin are a population with a significant unmet medical need, and alternative systemic therapy options in combination with RT are urgently needed. Clinical guidelines and consensus documents have provided definitions for cisplatin ineligibility; however, areas of debate include thresholds for age and renal impairment and criteria for hearing loss. Furthermore, the proportion of patients with resected LA SCCHN who are cisplatin ineligible remains unclear. Because of a scarcity of clinical studies, treatment selection for patients with resected, high-risk LA SCCHN who are deemed ineligible to receive cisplatin is often based on clinical judgment, with few treatment options specified in international guidelines. In this review, we discuss considerations related to cisplatin ineligibility in patients with LA SCCHN, summarize the limited clinical evidence for adjuvant treatment of patients with resected high-risk disease, and highlight ongoing clinical trials that have the potential to provide new treatment options in this setting.