Among disorders of the gastrointestinal tract diseases of the pancreas emerge due to their therapeutic difficulties and high mortality causing a major healthcare burden. Major bottlenecks of the field are the limited access to human tissue, the incomplete understanding of human pancreatic pathology and lack of human-relevant disease models. These limitations severely hinder translational pancreatic research and the development of effective therapy. To overcome these issues, novel advanced disease models with significant human relevance are crucially needed. Our group extensively uses pancreatic ductal organoids to study epithelial physiology and pathophysiology. A major breakthrough was the development of human pancreatic ductal organoids with controlled polarity by removing the extracellular matrix, which switches the orientation from apical-in to apical-out. This modification eliminates intraluminal pressure and provides direct access to the apical membrane, a long-standing limitation in studying ductal physiology. The polarity-switched organoids exhibit more stable intracellular calcium levels, improved assay sensitivity for forskolin-induced swelling, and enabled the discovery of previously unrecognized ion channels in ductal cells, including the calcium-activated chloride channel ANO1 and the epithelial sodium channel ENaC. Parallel work with mouse pancreatic ductal organoids demonstrated that these cultures closely replicate native ductal tissue in morphology, gene expression, and ion transport activity, offering a robust alternative to traditional duct isolation. Another major innovation is the establishment of human pluripotent stem cell-derived pancreatic duct-like organoids (PDLOs) that are homogeneous, polarized, and structurally, transcriptionally, proteomically, and functionally similar to in vivo ducts. These PDLOs can further mature upon transplantation into mice, forming complex ductal tissue and revealing distinct subpopulations, such as MUC1- versus CFTR-expressing ducts. Importantly, the hPSC-derived system supports precise genetic engineering, allowing the modeling of disease-relevant mutations such as KRAS, GNAS, and CDKN2A loss to recapitulate specific dysplastic and neoplastic pathways. Together, these developments bridge the gap between conventional cell lines or animal models and human pathophysiology, providing versatile, physiologically relevant platforms for basic research, drug discovery, and precision oncology.