Head and neck cancer (HNC) is the seventh most common malignancy affecting humans worldwide. HNC includes tumors of the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, and salivary glands, with the predominant histology being squamous cell carcinoma (SCC). Key risk factors include advanced age, environmental exposures including tobacco, and viral infections such as human papillomavirus (HPV). While HPV-related oropharyngeal cancer has a generally favorable prognosis, recurrence rates approach 50% for locally advanced HPV-negative HNC. Definitive chemoradiation or surgery followed by adjuvant radiotherapy or chemoradiation has been the standard of care for >15 years, and responses to immunotherapy in recent studies have been largely disappointing. Research that improves understanding of HNC biology is critical for developing novel treatment strategies, and preclinical studies in animal models that recapitulate human disease are essential for the successful translation of basic science findings to improve clinical outcomes. Despite recent advances in rodent models of HNC, several limitations remain that can potentially be overcome through research in companion animals with spontaneous HNC. This chapter reviews the substantial overlap in etiology, biology, and clinical management of HNC in humans, dogs, and cats.