02052nas a2200217   4500000000100000000000100001008004100002260001500043653002100058653001100079653002600090653002700116653001500143100002600158700001700184245005700201856005500258300000900313520149800322022001401820       2026                            d  c2026-05-1110aAdult Stem Cells10aCancer10aMechanisms of disease10aPluripotent Stem Cells10aStem cells1 aAmanda Andersson-Rolf1 aHans Clevers00aNew developments and applications of human organoids  uhttps://www.nature.com/articles/s41580-026-00974-0  a1-163 aOrganoid technology offers unique opportunities for studying human biology and disease in vitro. Organoids are self-organizing 3D structures, derived from pluripotent or tissue-resident stem cells that recapitulate key aspects of primary tissues. Compared with classical cell lines, organoids provide distinct advantages. They can be derived from both healthy tissues and diseased tissues, enabling the investigation of disease mechanisms and the development of personalized therapies, and they better recapitulate the cellular heterogeneity of the native tissue, allowing for better modelling of human (patho)physiology. Although current organoids have provided valuable insights, these insights are inherently reductionist and do not fully capture the complexity of human tissues. The research field is, therefore, moving towards next-generation models that more accurately represent the intricate cellular interactions, tissue architecture and microenvironmental cues that underlie human biology and disease. In this Review, we outline the limitations and challenges of current organoid systems, highlight recent advances aimed at increasing their complexity, and discuss innovations that support their translation into clinical applications. The focus is on human tissue stem cell-derived organoids, with comparisons to pluripotent stem cell-derived organoids where relevant. We conclude by identifying key factors and remaining challenges for developing the next generation of organoids.  a1471-0080