Patients with head and neck cancer often present with complex challenges due to a substantial comorbidity burden, including substance use disorders, and the tumor's location in regions that are both cosmetically and anatomically sensitive. These challenges can be categorized into 6 areas, that is, overall health (eg, performance status, biological age), physiological life stages (eg, aging), organ dysfunctions (including autoimmune comorbidities, organ transplants, and psychiatric disorders), previous and concurrent malignancies, previous and current therapies, and adherence to therapy. We provide a practical guide to help physicians understand and address the phenotypic multitude of potential complications in the management of these patients. The process has 4 main phases involving identification of the clinical challenge, understanding the reasons for ineligibility (contraindications), assessment of the risk to benefit ratio, and finally making informed decisions about systemic treatment. Proactive interventions, including prehabilitation, are crucial for optimizing patient outcomes and reversing some ineligibility issues. The evidence supporting contraindications is drawn from both clinical trials and real-world data, each with its strengths and limitations. These contraindications are applied as absolute or relative and further refined by expert opinions and consensus statements. There are 2 main reasons for ineligibility for a given treatment, absence of supporting data or negative outcome data. In these cases, careful interpretation using all levels of clinical evidence, including extrapolation and preclinical rationale, is essential. By mastering these skills, that may in the future be enhanced by artificial intelligence methods, significant advancements in patient care can be achieved.