To make a definitive diagnosis of skin cancer, dermatologists have been required to obtain skin biopsy specimens of suspicious lesions and to examine tissue pathologic abnormalities ex vivo under light microscopy. In the past decades, high diagnostic sensitivity, which is associated with a low biopsy threshold,1 has been increasingly emphasized in skin cancer screening to combat melanoma deaths and to counter the rising incidence and morbidity of nonmelanoma skin cancer. Distinguishing malignant from benign lesions, however, has always been associated with biopsies of innocuous mimickers of skin cancer, such as nevi and seborrheic keratoses. A 2012 international 10-year multicenter study,2 for example, estimated that 28.4 nevi are biopsied for every melanoma detected. These procedures have been accepted and rationalized as a “cost of doing business”—that is, our accepted set point on a receiver operating characteristic curve that aims to maximize sensitivity for melanoma diagnosis at the expense of specificity.