Disease management of head and neck cancer has improved significantly. However, a high rate of early recurrences and metastasis still counteract improvement of long-term survival. Hence, the quest for molecular mechanisms and key regulatory factors exploitable by targeted therapies is still ongoing. Such potential candidates may include also nuclear receptors, belonging to a superfamily of transcription factors implicated in a broad spectrum of physiological and pathophysiological processes. As dysfunction of nuclear receptor signaling contributes to a variety of proliferative diseases, they are major targets for drug discovery and hold promising potential for the development of improved anticancer treatment strategies. Several nuclear receptors have also been associated with head and neck cancer, and strategies targeting these molecules are currently tested in clinical trials. However, reports and molecular knowledge on the pathobiological relevance of nuclear receptors for cancers of the head and neck is currently rather fragmented. Hence, this review provides a general overview of nuclear receptors' molecular functions and summarizes their potential prognostic and therapeutic relevance for this tumor entity.