ABSTRACT: Clinicopathologic correlation is crucial to the correct diagnosis of disorders of the nail unit. This chapter will explore four common clinical scenarios and how pathology can help differentiate between their various etiologies. These include: dark spot on the nail plate (melanin versus heme), subungual hyperkeratosis (onychomycosis versus psoriasis), longitudinal melanonychia (benign versus malignant), and verrucous papule (verruca versus squamous cell carcinoma). Consideration must be given to both when to perform a biopsy and the location of the biopsy site, which must be based on an understanding of the origin of the changes. An overarching principle is that lesions within the same differential diagnosis may be present concomitantly, such as malignant melanoma of the nail unit associated with hemorrhage. Therefore, even with a biopsy-proven diagnosis, the clinician must always monitor lesions of the nail unit for appropriate response to treatment and consider an additional biopsy for recalcitrant lesions.