PURPOSE OF REVIEW: Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains a significant therapeutic challenge due to its biological complexity and clinical heterogeneity. This review addresses the relevance of exploring novel therapeutic approaches, particularly in light of recent advances and the persistent unmet needs in patient outcomes. RECENT FINDINGS: Recent phase II and III clinical trials have highlighted promising strategies, including combinations of immunotherapy with targeted therapies, antibody-drug conjugates (ADCs), HPV vaccines, dual immunotherapy approaches, and therapies targeting the tumor microenvironment. These innovations represent emerging directions to overcome resistance mechanisms and improve treatment efficacy. SUMMARY: The findings suggest that integrating innovative strategies such as ADCs, immunotherapy combinations, and tumor microenvironment-targeting therapies may significantly enhance clinical outcomes for patients with R/M HNSCC. Further research is essential to refine these approaches and optimize their application in clinical practice.