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These drugs target various therapeutic areas including non-small cell lung cancer, advanced or metastatic breast cancer, glioma, relapsed or refractory acute leukemia, urinary tract infection, Staphylococcus aureus bloodstream infections, nonalcoholic steatohepatitis, primary biliary cholangitis, Duchenne muscular dystrophy, hypertension, anemia due to chronic kidney disease, extravascular hemolysis, primary axillary hyperhidrosis, chronic obstructive pulmonary disease, severe alopecia areata, WHIM syndrome, Niemann\u2013Pick disease type C, schizophrenia, supraventricular tachycardia, congenital adrenal hyperplasia, and cystic fibrosis. Among these approved small-molecule drugs, those with unique mechanisms of action and designated as breakthrough therapies by the FDA represent a significant proportion, highlighting ongoing innovation. Notably, eight of these drugs (including Rezdiffra\u00ae, Voydeya\u00ae, Iqirvo\u00ae, Voranigo\u00ae, Livdelzi\u00ae, Miplyffa\u00ae, Revuforj\u00ae, and Crenessity\u00ae) are classified as \u201cfirst-in-class\u201d and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development.<\/jats:p>","DOI":"10.3390\/ph18050729","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T09:58:27Z","timestamp":1747303107000},"page":"729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Game Changers: Blockbuster Small-Molecule Drugs Approved by the FDA in 2024"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3185-0257","authenticated-orcid":false,"given":"Zhonglei","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Green Natural Products and Pharmaceutical Intermediates, Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China"},{"name":"School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus, Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Physics and Physical Engineering, Qufu Normal University, Qufu 273165, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Physics and Physical Engineering, Qufu Normal University, Qufu 273165, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Green Natural Products and Pharmaceutical Intermediates, Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5026-2808","authenticated-orcid":false,"given":"Liyan","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Physics and Physical Engineering, Qufu Normal University, Qufu 273165, China"},{"name":"Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Agrawal, S., Park, E., and Kluetz, P.G. 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