This study presents chances and challenges associated with the application of organic micro-pollutants (OMPs) as indicators in karst system characterization. The methodology and options of possible indications were evaluated based on the interpretation of the spatial distribution of 54 compounds in groundwater in combination with a complex geological setting consisting of multiple aquifer horizons and tectonic faults. A high variety of OMPs are released mainly in an urban area leading to concentrations of several nanograms per liter up to micrograms per liter, which are detectable using a high-performance liquid chromatography with subsequent tandem mass spectrometry (HPLC-MS/MS) method. Since characteristic patterns of spatial distribution were repeatedly observed during a 2-year observation period, important criteria of the aforementioned indicator application are fulfilled. Triazoles, compounds with recent high emission rates, could be successfully applied for the identification of flow directions and the delineation of catchment areas. Concentrations and the number of OMPs are believed to be dependent on properties of covering rock layers. Therefore, OMPs can also be used as a validation tool for vulnerability mapping. Compounds, such as triazines, persistent in the system for more than two decades, demonstrate the interaction between different parts of the aquifer system and the hydraulic characteristics of a tectonic fault zone. Such indicator potentials complement those of artificial tracer tests. Point sources of OMPs and their impact on groundwater could be identified qualitatively. In combination with the interpretation of the geological setting, the distribution of OMPs provides essential information for the development of a conceptual hydrogeological model.