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Methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) has emerged as a valuable diagnostic, prognostic, and therapeutic biomarker in modern oncologic pathology, primarily serving as a surrogate for CDKN2A/B homozygous deletion due to their close genomic proximity at chromosome 9p21. This review aims to systematically evaluate the clinical utility, diagnostic accuracy, and technical limitations of MTAP IHC across a diverse spectrum of human malignancies, while contextualizing its role within current molecular testing algorithms. We first examine the established diagnostic and grading performance of MTAP loss in central nervous system neoplasms and thoracic tumors, particularly malignant pleural mesothelioma, followed by an analysis of its emerging prognostic value in gastrointestinal, cutaneous, and genitourinary malignancies. Furthermore, we discuss the therapeutic implications of MTAP deficiency, focusing on the biological consequences of methylthioadenosine accumulation and the resulting synthetic vulnerabilities in the PRMT5/MAT2A pathway. By synthesizing diagnostic precision, prognostic relevance, and translational therapeutic insights, this review provides a comprehensive framework for integrating MTAP IHC into routine surgical pathology workflows and personalized oncology.