Approximately 1 in 5 Americans will develop skin cancerSkin cancer in their lifetime. Skin cancer develops when DNA damage triggers mutationsMutations in keratinocytes leading to their uncontrolled growth and potential malignant tumor formation. Basal cell carcinomaBasal cell carcinoma (BCC) and squamous cell carcinomaSquamous cell carcinoma (SCC) are the two most common keratinocyte carcinomas and frequently develop in skin areas exposed to harmful ultraviolet radiation (UVR). In addition to UVR, the development of BCC and SCC may be impacted by environmental, behavioral, and genetic risk factors. While the mortality rate for BCC and SCC is lower than melanomaMelanoma, a significant number of these cancers fall into the aggressive category, capable of invading regional structures, recurring, and metastasizing. These features, combined with the financial burden of skin cancer to both patients and healthcare systems, highlight the importance of skinSkin cancer screening to identify and diagnose those at higher risk of developing skin cancer. One of the challenges in screening for NMSCNon-melanoma skin cancer is the low diagnostic accuracy upon primary examination. Clinically, BCC and SCC are variable and may be difficult to distinguish from benign lesions using visual examination alone; thereby requiring potentially unnecessary biopsies to facilitate the diagnosisDiagnosis. In addition to visual examination, biomarkersBiomarkers may provide a more objective measure to provide clinically relevant information for patients’ diagnosis, prognosis, risk/susceptibility assessments, and the response to therapy. This chapter reviews our current understanding of biomarkers that have been identified in BCCBasal cell carcinoma and SCCSquamous cell carcinoma as well as their promise for improving disease diagnosis, pathogenesis, and treatmentTreatment.