<p>This review examines Japan’s 2025 revision of bioequivalence (BE) guidelines for semi-solid topical dermatological drug products as a case study in regulatory science, focusing on how accumulated scientific evidence has been translated into regulatory decision-making frameworks, which scientifically refines Japan’s long-standing dermatopharmacokinetic (DPK)-centered framework. Unlike prior studies primarily surveying regulatory documents, this review provides an in-depth analysis of the scientific rationale behind the revised Japanese framework, including the repositioning of DPK studies and introduction of Q1/Q2/Q3-based evaluation principles. The revision builds on two decades of domestic experience accumulated through collaborations among regulatory authorities, dermatological experts, and academic researchers, reflecting a balanced evolution rather than the mere adoption of overseas trends. A range of BE evaluation methodologies, including clinical endpoint, pharmacodynamic (PD), DPK, and in vitro studies, are briefly outlined, highlighting their regulatory context and current trends. Special attention is given to the evolving role of in vitro testing and the mechanistic understanding of formulation attributes, which support a paradigm shift toward a more science-based, product-specific BE strategy. By comparing regulatory approaches across Japan, the European Union, and the United States, this review elucidates the key similarities and divergences, offering insights for future regulatory convergences. This science-driven reform in Japan is expected to enhance both the regulatory rigor and efficiency of pharmaceutical development, thereby supporting patient access to high-quality, affordable generic semi-solid topical dermatological drug products.</p>