Sampling the nail unit for histopathologic analysis is often an important component of the diagnosis of nail disease, whether inflammatory, infectious or neoplastic. While skin biopsy is usually relatively straightforward, the nail unit presents some challenges in this regard. The physical properties of the hard keratin nail plate make biopsy access, specimen submission and processing more complicated. These limitations can greatly affect the quality of the specimen available for interpretation by the pathologist. This chapter will explore some of the techniques commonly used in the analysis of nail unit specimens and offer some ways to improve outcomes to optimize diagnostic success.