More than 30% of Europe’s land surface is made up of karst exposures. In some countries, water from karst aquifers constitutes almost half of the drinking water supply. Hydrological simulation models can predict the largescale impact of future environmental change on hydrological variables. However, the information needed to obtain model parameters is not available everywhere and regionalization methods have to be applied. The responsive behaviour of hydrological systems can be quantified by individual metrics, so-called system signatures. This study explores their value for distinguishing the dominant processes and properties of five different karst systems in Europe and the Middle East. By defining ten system signatures derived from hydrodynamic and hydrochemical observations, a processbased karst model is applied to the five karst systems. In a stepwise model evaluation strategy, optimum parameters and their sensitivity are identified using automatic calibration and global variance-based sensitivity analysis. System signatures and sensitive parameters serve as proxies for dominant processes, and optimised parameters are used to d ... mehretermine system properties. By sensitivity analysis, the set of system signatures was able to distinguish the karst systems from one another by providing separate information about dominant soil, epikarst, and fast and slow groundwater flow processes. Comparing sensitive parameters to the system signatures revealed that annual discharge can serve as a proxy for the recharge area, that the slopes of the high flow parts of the flow duration curves correlate with the fast flow storage constant, and that the dampening of the isotopic signal of the rain as well as the medium flow parts of the flow duration curves have a non-linear relation to the distribution of groundwater storage constants that represent the variability of groundwater flow dynamics. Our approach enabled us to identify dominant processes of the different systems and provided directions for future large-scale simulation of karst areas to predict the impact of future change on karst water resources.