The LAST Project codified the now well-established biological principles that divide human papillomavirus–associated diseases of the lower anogenital tract into 2 distinct classes: low-grade lesions indicative of a human papillomavirus’ vegetative life cycle and high-grade lesions that confer risk of cancer (ie, precancer). Unfortunately deciding between infection and precancer can be problematic in the real world in which we practice. Obtaining additional biological information might be very useful in aiding the observer to identify cases with true cancer risk and to exclude cases that are best managed more conservatively. To this end, the LAST Project was charged with reviewing the scientific literature to determine if any biomarkers were available to aid pathologists in rendering a more precise and reliable diagnostic interpretation. This report takes a case-based approach to the biomarker recommendations of the LAST Project.