Melanocytic neoplasms range from benign nevi to malignant melanomas, and accurate differentiation between these lesions is crucial for effective treatment. Among the various immunohistochemical markers available, PRAME (Preferentially Expressed Antigen in Melanoma) has emerged as a significant diagnostic tool in the evaluation of melanocytic lesions due to its high sensitivity and specificity, particularly in distinguishing malignant melanomas from benign nevi. PRAME is strongly expressed in malignant melanomas, including cutaneous, uveal, and mucosal variants, while its expression is minimal or absent in benign and dysplastic nevi. Its utility extends to identifying metastases, especially in difficult-to-diagnose cases such as metastatic melanoma, where it aids in differentiating melanoma from other malignancies. Additionally, the presence of PRAME is associated with poor prognosis, as higher expression levels correlate with increased metastatic risk. Despite its effectiveness, the use of PRAME in immunohistochemistry is not without limitations. It is not exclusive to melanoma, as its expression can be seen in some non-melanocytic tumors, which may reduce its specificity in certain cases. Nevertheless, PRAME remains a valuable tool in the diagnostic and prognostic evaluation of melanocytic lesions, particularly when histological features are unclear or ambiguous. Further research is needed to refine its role in different melanoma subtypes and to explore its potential as a target for immunotherapy.