CD44, the product of a single gene, exists as several isoforms generated by alternative exon splicing and posttranslational modifications, and is widely distributed in different cells and tissues including those of squamocellular origin. CD44 is a cell surface glycoprotein involved in many cellular processes acting as a receptor for cell to cell or cell to matrix adhesion, as a signal transmitter and as a growth factor-presenting molecule. Numerous studies based on immunohistochemical analyses of paraffin-embedded or frozen tissue sections using different monoclonal antibodies to CD44 isoforms and molecular biological techniques have provided evidence that in many types of tumours there is overexpression of CD44 isoforms and aberrant processing of immature CD44 transcripts relative to non-neoplastic control tissues, suggesting a role of CD44 in tumour development and progression. In contrast to these malignancies, one or more of the CD44 splice-variant isoforms are down-regulated in squamous cell carcinomas of the head and neck. CD44-deficient mice develop normally without giving rise to spontaneous tumours, but CD44-negative cells appear to be more susceptible to oncogenic transformation. Reduction in the expression of CD44 may confer growth advantage and malignant properties to tumour cells. The clinical significance of CD44 in squamous cell carcinomas of the head and neck as a tumour marker for cancer diagnosis and prognosis is discussed.