Oral squamous cell carcinoma (OSCC) represents 95% of all cancers of the head and neck region. Tumour hypoxia, the situation where tumour cells have been deprived of oxygen, has proven to play a pivotal role in this neoplasm. The aim of this review is to explore the composition of hypoxia pathway in OSCC, particularly the clinical and pathological implications of hypoxia-related proteins by immunohistochemistry (IHC) techniques, and also to evaluate the possible usefulness of hypoxia-related interactions for OSCC therapy. Hypoxia regulatory networks seem to be a hallmark of OSCC pathophysiology becoming a growing challenge to design new studies and strategies from biology to clinical applications. The present chapter identified the clinical application of hypoxia-related IHC-based candidate biomarkers with a focus on OPMDs malignant transition and OSCC prognosis. Furthermore, we propose that targeting therapies to hypoxia could be a promising strategy to improve the outcomes of patients with OSCC. To sum up, the effect of hypoxia in OSCC represents an interesting avenue for future research.