Purpose of Review <p>Head and neck squamous cell carcinoma (HNSCC) is a global malignancy characterised by extremely low survival rates, primarily contributed to by late diagnosis, tumour heterogeneity, and resistance to available therapies. Deciphering reliable biomarkers is crucial for early diagnosis, prognosis and personalized therapy. This review discusses the possibilities of clusterin (CLU) as an emerging biomarker in the field of HNSCC therapeutics by incorporating insights derived from preclinical, clinical and proteomic data.</p> Key Findings <p>The expression of CLU in HNSCC cases has been found to be correlated with advanced stages of the tumour, metastatic potential higher histological grades and therapeutic resistance. Mechanistic studies demonstrate that CLU plays a dual role in enhancing tumour cell survival and facilitating apoptosis, contingent upon isoform and environmental context. Recent findings confirm the effectiveness of CLU as a biomarker for early diagnosis, risk evaluation, and forecasting therapeutic response. This review also focuses on the comparison of CLU to known HNSCC biomarkers and stresses the progress made in non-invasive screening and targeted therapies.</p> Summary <p> In conclusion, CLU shows strong potential as a biomarker and therapeutic target, warranting further research for clinical application in HNSCC.</p> Graphical Abstract <p></p>