Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of the oral cavity, pharynx, and larynx. It is classified into HPV-negative and HPV-positive subtypes, with the latter increasingly linked to human papillomavirus (HPV) infection, particularly HPV-16. HNSCC is the sixth most common cancer globally, with 890,000 new cases and 450,000 deaths in 2018. Risk factors include tobacco use, alcohol consumption, HPV infection, and environmental pollutants. HPV-positive HNSCC has a better prognosis than HPV-negative HNSCC, and treatment options include surgery, chemotherapy, and radiation. Immune checkpoint inhibitors like pembrolizumab and nivolumab are FDA-approved for recurrent or metastatic HNSCC. Molecular studies have identified key genetic and epigenetic alterations, including mutations in TP53, CDKN2A, and PIK3CA, which contribute to HNSCC progression. The tumour microenvironment plays a critical role in HNSCC development, with immune evasion mechanisms such as immunosuppressive factors and PDL1 expression. Metastasis is driven by epithelial-mesenchymal transition (EMT), MMPs, and hypoxia. Diagnosis involves biopsy and histopathological analysis, with p16INK4A testing useful for identifying HPV-positive HNSCC. Screening and prevention strategies include reducing tobacco use, improving oral health, and HPV vaccination. Early detection is crucial, as most HNSCC cases are diagnosed at advanced stages without a pre-malignant lesion. Treatment is typically multimodal, with surgery, chemotherapy, and radiation as primary options. Ongoing research aims to improve therapeutic strategies through biomarker identification and targeted therapies.Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of the oral cavity, pharynx, and larynx. It is classified into HPV-negative and HPV-positive subtypes, with the latter increasingly linked to human papillomavirus (HPV) infection, particularly HPV-16. HNSCC is the sixth most common cancer globally, with 890,000 new cases and 450,000 deaths in 2018. Risk factors include tobacco use, alcohol consumption, HPV infection, and environmental pollutants. HPV-positive HNSCC has a better prognosis than HPV-negative HNSCC, and treatment options include surgery, chemotherapy, and radiation. Immune checkpoint inhibitors like pembrolizumab and nivolumab are FDA-approved for recurrent or metastatic HNSCC. Molecular studies have identified key genetic and epigenetic alterations, including mutations in TP53, CDKN2A, and PIK3CA, which contribute to HNSCC progression. The tumour microenvironment plays a critical role in HNSCC development, with immune evasion mechanisms such as immunosuppressive factors and PDL1 expression. Metastasis is driven by epithelial-mesenchymal transition (EMT), MMPs, and hypoxia. Diagnosis involves biopsy and histopathological analysis, with p16INK4A testing useful for identifying HPV-positive HNSCC. Screening and prevention strategies include reducing tobacco use, improving oral health, and HPV vaccination. Early detection is crucial, as most HNSCC cases are diagnosed at advanced stages without a pre-malignant lesion. Treatment is typically multimodal, with surgery, chemotherapy, and radiation as primary options. Ongoing research aims to improve therapeutic strategies through biomarker identification and targeted therapies.