Skin cancer is the most common malignancy in humans, likely due to its location at the interface between internal and external environments and exposure to multiple carcinogens, mostly ultraviolet radiation (UVR) and human papillomaviruses (HPV). With increased longevity, changing patterns of sun exposure and greater UVR reaching the earth's surface due to ozone depletion, the incidence of skin cancer is steadily increasing worldwide. Moreover, skin cancer, mostly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (collectively known as non-melanoma skin cancer (NMSC), is a substantial public health concern and one of the largest Medicare health expenditures. Individuals presenting with skin cancer are at high risk for synchronous and metachronous second primary skin cancers. This phenomenon is known as "field cancerization", where the entire cutaneous site affected is presumed to be mutagenized and is therefore at risk for multiple cancers. The recent application of molecular technologies to the examination of peri-lesional and more distant adjacent normal skin samples has demonstrated many of the genotypic aberrations found in cancer. These defects are the earliest changes of oncogenesis that occur in a stepwise, cumulative fashion culminating in metastatic cancer via initiation, promotion, selection, and clonal expansion. Moreover, these findings implicate two distinct levels of field cancerization: 1) molecular progression where histologically normal cells accumulate genomic damage; and 2) phenotypic progression denoted by evolution of histologically normal skin to precursors to in situ cancer that can be followed by invasion and ultimately metastatic disease. Phenotypic progression is also characterized by the expansion of genetically damaged tumor cells in the modified environment that facilitate tumor growth and suppress the host response. In this model, the cutaneous field develops a "tumor stem cell", which acquires a growth advantage and exhibits a "mutator phenotype" [i.e. genomic instability (GIS)] that enables it to expand beyond its histologically defined stem cell niche, form diverse clonal fields, and accrue further genetic alterations that eventuate into invasive cancer. GIS is manifested as single base mutations, gain or loss of whole or partial chromosomes, amplification of oncogenes, mismatch repair gene defects, and epigenetic alterations including hypermethylation of promoter DNA of key tumor suppressor genes, or genomic incorporation of the oncogenic HPV. The facilitating environment for tumor growth represents the local production of factors that allow the tumor cells to escape the immune system, to leave the tumor stem cell niche and expand into the surrounding environment. In this chapter, we review the epidemiologic evidence of field cancerization; etiologic factors that lead to genomic instability in the skin; the stem cell niche where cancer-causing genetic defects are most likely to be initiated, and from which the mutated clone must expand beyond; host factors that augment and accelerate the process such as immunosuppression; and the growing body of evidence that supports the concept of cutaneous field cancerization. Moreover, we discuss the potential utilization of field effect biomarkers in risk assessment, cancer prevention, margin control, and prognosis. © 2011 by Nova Science Publishers, Inc. All rights reserved.