Background <p>The landscape of in vitro models has evolved from simple two dimensional (2D) cultures to three-dimensional (3D) organoids and multi-organ microphysiological systems. Early monolayer cultures enabled directed differentiation but provided limited physiological relevance.</p> Main Body <p>The development of organoid technology is a significant invention, which allows the cells to self-organize into complex 3D structures to recapitulate the cell diversity, architecture and functions of natural tissues. This has enabled more effective modelling of patient-specific diseases and processes. The latest development of the multi-organ microphysiological systems, integrates organoids or engineered tissues with microfluidic channels through which nutrients are perfused, and blood flow as well as mechanical stimuli are mimicked. This technology provides precise control over the tissue microenvironment to facilitate dynamic cell interactions and communication among different tissue types.</p> Conclusion <p>These platforms more precisely mimic human biological processes, thereby improving disease modelling, drug screening, and the development of tissue grafts for regenerative therapies. This review discusses the evolution from 2D monolayer cell cultures, through the formation of organoids, to the engineering of organ-on-a-chip systems. It underlines how these technologies have advanced regenerative therapies by enhancing the ability to repair or replace damaged tissues and precision medicine through the creation of patient-specific disease models and personalized treatment strategies. Importantly, this review provides a comparative critical assessment of the functional capabilities, limitations, and translational readiness of each platform, identifying the specific contexts in which each system excels or falls short of its alternatives.</p> Graphical Abstract <p></p>