Drug repurposing, also known as drug repositioning or reprofiling, has emerged as a highly transformative strategy in modern pharmaceutical research, providing an efficient and economical alternative to traditional de novo drug discovery processes. Traditional drug development pipelines require 10 to 15 years and financial investments exceeding two billion dollars, while repurposingmakesefficient use of pre-existing clinical safety, pharmacokinetic, and toxicological profiles. This strategy significantly compresses development timelines to 5 to 7 years and drastically cuts down research expenses. This comprehensive review examines the major core methodologies driving the field and categorizing them systematically into ligand-based drug-oriented, structure-based target-oriented, and network-driven disease-oriented approaches. It details how recent advancements in computational biology, artificial intelligence, high-throughput phenotypic screening, molecular docking, and multi-omics data analytics have collectively accelerated the precise identification of novel drug-disease correspondences. The paper provides an in-depth analysis of landmark historical case studies, including Sildenafil, Aspirin, Thalidomide, and Metformin, showing their successful clinical translation in different therapeutic areas, including oncology, psychiatry, immunology, and emerging infectious diseases like COVID-19.Despite many clinical advantages, widespread adoption faces critical bottlenecks. These include the inherent biological complexity of heterogeneous diseases, limited intellectual property protections for generic or off-patent medications, complex regulatory frameworks, and data integration limits. This review balances these major advantages against remaining structural challenges, highlighting that robust interdisciplinary collaboration between academia, pharmaceutical industries, public health bodies, and international regulatory agencies is absolutely imperative to systematically unlock the full therapeutic potential of existing chemical libraries and expand global healthcare resources. Drug repurposing stands as acrucial tool for fast-tracking therapeutic solutions and addressing global health inequities.
