We propose a systematic framework for delineating Hydrological Response Units (HRUs), based on a modified Curve Number (CN) approach. The CN-value accounts for three major physiographic characteristics of a river basin, by means of classes of soil permeability, land use/land cover characteristics, and drainage capacity. A semi-automatic procedure in a GIS environment allows producing basin maps of distributed CN-values as the product of the three classified layers. The map of CN-values is used in the context of model parameterization, in order to identify the essential number and spatial extent of HRUs and, consequently, the number of control variables of the calibration problem. The new approach aims at reducing the subjectivity introduced by the definition of HRUs, and simultaneously at providing parsimonious modelling schemes. In particular, the CN-based parameterization (1) allows the user to assign as many parameters as can be supported by the available hydrological information, (2) associates the model parameters with anticipated basin responses, as quantified in terms of CN classes across HRUs, and (3) reduces the effort for model calibration, simultaneously ensuring good predictive capacity. The advantages of the proposed framework are demonstrated in the hydrological simulation of Nedontas river basin, Greece, in which parameterizations of different complexities are employed in a recently improved version of the HYDROGEIOS modelling framework.