Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide and accounts for 95% of the head and neck cancer cases in the Western world. Over the past three decades advancements in management have produced equivocal survival benefits. We have used complementary DNA microarrays containing 9,216 genes to monitor gene expression in HNSCC tissue samples, adjacent normal margins and lymph node metastases. We extracted RNA from 46 surgically resected HNSCC tumor samples and compared it with cultured normal human adult keratinocytes. We are also comparing at least ten additional matched samples of primary and metastatic tumors from these same patients. Hierarchical clustering methodology has allowed us to classify these tumors on the basis of their gene expression patterns, and we are currently correlating these results with the clinical data collected for each patient. We have identified a group of genes that are generally overexpressed in these tumors, as well as genes that are diagnostic of specific tumor subtypes. Our results demonstrate that it is possible to classify HNSCC tumors based solely on global patterns of gene expression and to identify candidate genes that are the best predictors of tumor subtypes. We are studying these genes using other methodologies, such as tissue microarrays, to examine further their suitability as possible targets for drug treatment.