Purpose of review: There is no general agreement on which diagnostic procedures are required and optimal in searching for primary tumors among patients with cervical metastasis of unknown primary (CUP). Because of the rising incidence of human papillomavirus (HPV)-associated oropharyngeal carcinoma, it is reasonable to assume that the number of small oropharyngeal tumors with neck metastasis will increase. The purpose of this review is to highlight the diagnostic approaches more useful in detecting such lesions.

Recent findings: After the introduction of the narrow band imaging technique, positron emission tomography-computed tomography, and transoral diagnostic procedures, the accuracy in discovering the primary lesion is up to 80–90%. By far, most primaries arise in the oropharynx, especially among patients with p16/HPV-positive CUP.

Summary: The oropharynx is the most likely primary site in patients with CUP, especially in p16/HPV-positive cases. By utilizing recent techniques, a high diagnostic accuracy in detecting the primary tumor is achievable; this may offer better survival rates with cost-effective efforts. We recommend some approaches for the diagnostic protocol used in searching for primary tumors in patients with CUP.