Microphysiological systems (MPS), including organ-on-chip platforms and complex organoid models, represent a transformative approach to human-relevant in vitro modeling. These technol-ogies bioengineer aspects of organ architecture and functionality, revolutionizing drug development, reducing animal testing, and enabling personalized medicine approaches. Despite significant advances, several critical challenges remain before their full potential can be realized. This article examines key obstacles facing MPS adoption and implementation while proposing actionable solu-tions to accelerate their development and acceptance. Major challenges include standardization issues across terminology and protocols, validation complexities requiring robust reference com-pounds and benchmarking standards, regulatory uncertainties regarding data requirements and qualification processes, and barriers to effective data sharing among stakeholders. The paper traces the field's evolution through various international initiatives, particularly highlighting the Center for Alternatives to Animal Testing's (CAAT) contributions, including the establishment of the International MPS Society and World Summits. Proposed solutions emphasize establishing global standards through international consortia, enhancing validation frameworks through specialized validation centers, fostering collaboration through pre-competitive consortia and standardized data formats, and advancing regulatory integration through detailed case studies and clear guidance documents. Future priorities focus on overcoming technical challenges in biological complexity, addressing engineering hurdles, standardizing technologies, improving data management, increasing eco-nomic accessibility, and integrating with other emerging technologies. The path forward requires coordinated, collaborative efforts across academia, industry, regulatory agencies, and technology suppliers to systematically address these interrelated challenges.