Conventional two-dimensional cell cultures and in vivo mouse models show significant limitations in drug discovery and development, as they do not adequately reflect the cellular complexity of human tissue. Particularly in oncology, they lack predictive power regarding tumor biology and therapy response. Thus, there is a need to develop more physiologically relevant models that capture the complexity of tumors and, at the same time, allow for the reduction of animal testing in accordance with the 3Rs principle. Organoids, three-dimensional cell aggregates with organ-like properties, offer promising alternatives. Patient-specific tumor organoids reflect the genetic heterogeneity of individual tumors and enable personalized therapeutic approaches. Organoid-on-chip models extend this approach by integrating organoids into microfluidic systems combining the spatial complexity of organoids with the technological precision of microfluidic systems and modeling organ interactions. In addition, ex vivo tumor explant models enable the cultivation of intact tumor tissue slices under controlled laboratory conditions. By preserving the natural tissue architecture and tumor microenvironment, tumor explants bridge the gap between highly standardized in vitro models and more complex in vivo models opening a venue for new perspectives in personalized cancer therapy.