This chapter discusses basic research in head and neck cancers, where head and neck squamous cell carcinoma (HNSCC) carries a high mortality rate despite advances in chemotherapy and radiation therapies. Cancer is the result of transformation from a normal to a malignant cell that results from accumulated mutations. Genetic alterations provide means of identifying tumor cells as well as defining changes that presumably determine biological differences from their normal counterparts. Fluorescence in situ hybridization (FISH) analysis of SCC in vivo (from histologic sections) has demonstrated that tumor karyotypes observed in established cell lines accurately reflect that of the tumor. Aberrant cancer genes rarely function independently and evidence points to a carefully choreographed interplay among gene products in the regulation of normal growth. Clonality refers to the property that the cells within a tumor are derived from a single parent cell.