Organoids are innovative three-dimensional and self-organizing cell cultures of various lineages that can be used to study diverse tissues and organs. Human organoids have dramatically increased our understanding of developmental and disease biology. They provide a patient-specific model to study known diseases, with advantages over animal models, and can also provide insights into emerging and future health threats related to climate change, zoonotic infections, environmental pollutants or even microgravity during space exploration. Furthermore, organoids show potential for regenerative cell therapies and organ transplantation. Still, several challenges for broad clinical application remain, including inefficiencies in initiation and expansion, increasing model complexity and difficulties with upscaling clinical-grade cultures and developing more organ-specific human tissue microenvironments. To achieve the full potential of organoid technology, interdisciplinary efforts are needed, integrating advances from biology, bioengineering, computational science, ethics and clinical research. In this Review, we showcase pivotal achievements in epithelial organoid research and technologies and provide an outlook for the future of organoids in advancing human health and medicine.