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CDKN2A encodes the tumor suppressor p16^INK4a protein, inactivated in up to 50% of human cancers, most commonly through homozygous deletion (HD). CDKN2A HD carries major diagnostic, prognostic, and grading implications across several central nervous system (CNS) tumor types and subtypes, as well as in other solid neoplasms, including melanoma and mesothelioma. Screening for this deletion is therefore part of the pathologist's daily routine. Multiple approaches are currently available for detecting CDKN2A alterations. In addition to fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH), several other molecular techniques have emerged, each with distinct strengths and limitations, underscoring the need for integrated diagnostic strategies. Here, we review the current literature on the diagnostic, grading and prognostic significance of CDKN2A HD in solid tumors with a focus on CNS neoplasms. We also review the emerging evidence on the clinical impact of alternative gene inactivation mechanisms, including hemizygous deletions and point mutations, and discuss the performance and limitations of currently available diagnostic assays for their detection. We finally propose a practical diagnostic workflow for achieving a reliable CDKN2A alteration assessment to support patient management and therapeutic decision-making.