The generation of scientific knowledge to inform environmental management is crucial with current rates of global change. Although ecology and river science in particular have advanced greatly in the last 40 years, gaps remain between what we know and what environmental managers need to know to protect and restore aquatic resources. We argue that detailed quantitative relationships among human activities, contaminants, habitat alterations, and ecosystem services are needed to fill many of these gaps. Given that detailed research efforts cannot be conducted on all water bodies of the planet, scientists need to develop methods for transferring these global change relationships (models) from one system and region to another. Complexity in global change relationships is caused by natural variation among rivers and variation among responses to human activities. We propose resolving this complexity with a set of guiding principles intended to facilitate transfer of knowledge learned in one river or region to another. The ecology of disturbance provides the theoretical framework for predicting effects of human activities on rivers as well as management activities. Predicting river responses to human activities is challenged by the diversity of contaminants and habitat alterations associated with these activities, but predicting effects of human activities can be improved by recognizing: similarities in sets of stressors within classes of human activities; similarities in how different stressors affect rivers; and distinguishing effects of stressors having direct versus indirect regulation of ecosystem services. Geology and climate are key variables for predicting ecological response to human activities because they regulate the natural variation in river structure and function as well as the human activities and corresponding sets of stressors in watersheds. Transferring relationships among systems can be facilitated by emphasis on direct rather than indirect relationships and developing predictions of how geology and climate regulate direct relationships in global change ecology. These guiding principles for predicting effects of human activities should be tested and refined to resolve complexity and to manage ecosystem services, which will emerge as an important currency for global assessment of ecosystems.