Nonmelanoma skin cancer (NMSC) represents the most common form of cancer in the human body. The method for diagnosing and treating NMSCs requires a skin biopsy that is processed and stained for analysis on a standard optical microscope. This process is painful for patients, and the invasiveness of biopsy introduces a delay into NMSC detection, which contributes to patient morbidity and adds substantial cost to the healthcare system. Zebra Medical Technologies (ZMT) aims to address the unmet clinical need for a better method to detect NMSCs earlier. In Phase I of this grant, ZMT demonstrated the feasibility of a portable, skin- imaging microscope for human clinical studies (Aim 1), developed software for data acquisition, image processing, and improved user interface (Aim 2), and demonstrated in 5 human subjects with basal cell carcinoma (BCC) the ability to detect pathologic features of BCC (Aim 3). ZMT has created the first fiber coupled multiphoton microscopy (MPM) system for in vivo imaging of skin cellular anatomy. Building on this success, ZMT will build clinical evidence in Phase II to support a 510(k) submission for United States Food & Drug Administration (FDA) clearance. This is a necessary and valuable step towards bringing this technology into regular clinical practice. In this proposal we will accomplish three aims: Aim 1) Advance development of the portable, skin-imaging microscope for a clinical trial, Aim 2) Develop library of slide images of targeted skin diseases comparing MPM to traditional histology, and Aim 3) Conduct in vivo human performance testing to support FDA clearance.