Reference hydrologic networks (RHNs) can play an important role in monitoring for changes in the hydrological regime related to climate variation and change. Currently, the literature concerning hydrological response to climate variations is complex and confounded by the combinations of many methods of analysis, wide variations in hydrology, and the inclusion of data series that include changes in land use, storage regulation and water use in addition to those of climate. Three case studies that illustrate a variety of approaches to the analysis of data from RHNs are presented and used, together with a summary of studies from the literature, to develop approaches for the investigation of changes in the hydrological regime at a continental or global scale, particularly for international comparison. We present recommendations for an analysis framework and the next steps to advance such an initiative. There is a particular focus on the desirability of establishing standardized procedures and methodologies for both the creation of new national RHNs and the systematic analysis of data derived from a collection of RHNs.