Real and apparent conflicts between ecosystem and human needs for fresh water are contributing to the emergence of an alternative model for conducting river science around the world. The core of this new paradigm emphasizes the need to forge new partnerships between scientists and other stakeholders where shared ecological goals and river visions are developed, and the need for new experimental approaches to advance scientific understanding at the scales relevant to whole-river management. We identify four key elements required to make this model succeed: existing and planned water projects represent opportunities to conduct ecosystem-scale experiments through controlled river flow manipulations; more cooperative interactions among scientists, managers, and other stakeholders are critical; experimental results must be synthesized across studies to allow broader generalization; and new, innovative funding partnerships are needed to engage scientists and to broadly involve the government, the private sector, and NGOs.