PRAME, a member of the cancer/testis antigen family, plays a significant role in skin cancer diagnostics, prognosis, and therapy. It is a nuclear receptor and transcriptional regulator that inhibits retinoic acid signaling, contributing to tumor progression. PRAME is highly expressed in melanoma, distinguishing it from benign nevi, and is associated with aggressive tumor phenotypes. Its expression is also observed in uveal melanoma, acral melanomas, and soft tissue sarcomas, aiding in differential diagnosis. In non-melanoma skin cancers like basal cell carcinoma and Merkel cell carcinoma, PRAME expression varies, leading to diagnostic challenges. PRAME's potential as a therapeutic target is being explored through immunotherapies, including T-cell-based therapies and vaccines. Its expression in mucosal melanomas correlates with poor prognosis, while in acral melanomas, it serves as a diagnostic marker with high sensitivity and specificity. PRAME expression in Spitzoid lesions is variable, requiring careful interpretation. In sebaceous carcinoma, PRAME lacks specific diagnostic value but may assist in grading. PRAME is a critical marker for undifferentiated melanoma and helps differentiate melanoma from clear cell sarcoma. Its role in melanoma diagnosis, prognosis, and immunotherapy is promising, with ongoing research aiming to enhance its clinical application. PRAME's expression varies across cancers, influencing treatment strategies and outcomes. Future studies and clinical trials will further explore its potential in melanoma management.PRAME, a member of the cancer/testis antigen family, plays a significant role in skin cancer diagnostics, prognosis, and therapy. It is a nuclear receptor and transcriptional regulator that inhibits retinoic acid signaling, contributing to tumor progression. PRAME is highly expressed in melanoma, distinguishing it from benign nevi, and is associated with aggressive tumor phenotypes. Its expression is also observed in uveal melanoma, acral melanomas, and soft tissue sarcomas, aiding in differential diagnosis. In non-melanoma skin cancers like basal cell carcinoma and Merkel cell carcinoma, PRAME expression varies, leading to diagnostic challenges. PRAME's potential as a therapeutic target is being explored through immunotherapies, including T-cell-based therapies and vaccines. Its expression in mucosal melanomas correlates with poor prognosis, while in acral melanomas, it serves as a diagnostic marker with high sensitivity and specificity. PRAME expression in Spitzoid lesions is variable, requiring careful interpretation. In sebaceous carcinoma, PRAME lacks specific diagnostic value but may assist in grading. PRAME is a critical marker for undifferentiated melanoma and helps differentiate melanoma from clear cell sarcoma. Its role in melanoma diagnosis, prognosis, and immunotherapy is promising, with ongoing research aiming to enhance its clinical application. PRAME's expression varies across cancers, influencing treatment strategies and outcomes. Future studies and clinical trials will further explore its potential in melanoma management.