Head and neck squamous cell carcinomas are among the most common neoplasms worldwide and characterized by local tumor aggressiveness, high rate of early recurrences, development of metastasis, and second primary cancers. Despite modern therapeutic strategies and sophisticated surgical management, overall survival-rates remained largely unchanged over the last decades. Thus, the need for novel treatment options for this tumor entity is undeniable. A key event in carcinogenesis is the uncontrolled modulation of genetic programs. Nuclear receptors belong to a large superfamily of transcription factors implicated in a broad spectrum of physiological and pathophysiological processes, including cancer. Several nuclear receptors have also been associated with head and neck cancer. This review will summarize their mode of action, prognostic/therapeutic relevance, as well as preclinical and clinical studies currently targeting nuclear receptors in this tumor entity.