Recent molecular genetic studies provide evidence that the majority of, if not all, head and neck squamous cell carcinomas (HNSCCs) develop within a contiguous field of preneoplastic cells. Cells of a field show genetic alterations associated with the process of carcinogenesis. A subclone in a field gives rise to an invasive carcinoma. An important implication of this knowledge is that, after surgery of the initial carcinoma, part of the field may remain in the patient. A field with preneoplastic cells that share genetic alterations with cells of the excised tumor has been detected in the resection margins of at least 25% of patients, indicating that this frequently occurs. Fields can be much larger than the actual carcinoma, sometimes having a diameter >7 cm. When a field remains after resection of the tumor, the risk for another carcinoma, designated as a second field tumor (SFT), is considerably greater. It is important to realize that an SFT develops from preneoplastic cells clonally related to the initial tumor. In this respect, it should be discriminated from a recurrent carcinoma that has developed from minimal residual cancer that was left behind and from a second primary tumor that independently develops from the initial carcinoma. Patients at risk for SFTs belong to a unique patient group for whom intense surveillance is indicated and chemoprevention is an attractive option. The priorities are to identify the patients in whom a remaining field will progress to cancer and to find the genes involved. With this knowledge, highly efficient clinical prevention trials, including those using the local application of therapeutic agents, can be designed. It is important to note that SFTs also may occur after treatment of various other cancers, including those of the bladder, skin, esophagus, lung, cervix, breast, and colon.