Research advances over the past decade have led to a changing perception of the natural history of head and neck cancer. For instance, we now have the capacity to quantify and characterize various environmental carcinogens bound to mucosal DNA. These DNA adducts provide a quantitative measure of a disease process which exists long before clinically defined cancer is recognized. Similarly, histopathologically normal mucosa within head and neck cancer patients is currently known to express multiple genetic abnormalities including increased cellular DNA content, mutations in cell regulatory genes, as well as alterations in growth factors and their associated receptors. These subclinical events may, likewise, be associated with aberrant cellular proliferation and differentiation which provide a target for subsequent therapy. Disease invasion and metastases is now seen as a heterogenous process involving a complex of factors intrinsic to both the host as well as the cancer. Most significantly, advanced disease is not simply defined by its size and location. Rather, the progression of head and neck cancer is a dynamic process characterized by increasing genetic instability leading to an accumulation of critical mutational events. A biologic basis for resistance to treatment is thus being defined. Treatment strategies based on these laboratory advances are emerging and involve monoclonal antibody targeting, cytokines produced through recombinant molecular technology, and gene therapy.