PURPOSE OF REVIEW: Relapsed or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a deadly disease that historically was treated with palliative chemotherapy-based regimens. Since 2019, immunotherapy-based regimens have become the standard of care for 1st line treatment in this disease. Over the last several years, there have been numerous studies conducted with novel combination therapies for R/M HNSCC but there has not yet been a new standard of care. RECENT FINDINGS: Novel treatment combinations with chemotherapy, targeted therapy, immunotherapy, vaccines, and intratumoral drugs have been evaluated in the treatment of R/M HNSCC. Favorable efficacy has been seen with many of these combinations, although some large studies have failed to improve upon the current standard. SUMMARY: Many promising combination regimens are being tested which could lead to a new standard of care in the treatment of R/M HNSCC in the coming years.