The CALFED Bay-Delta Program is an ambitious effort to restore ecosystems and improve reliability of ecosystem services in California’s Central Valley. Key issues for CALFED and its Ecosystem Restoration Program (ERP) include (1) meeting societal demand for multiple, potentially conflicting ecosystem services; (2) the tradeoff among more or less environmentally intrusive approaches to solving problems; (3) whether restoration should focus at the ecosystem level or on individual species; (4) the appropriate response to uncertainty; and (5) the tension between action and investigation. A long-term, landscape-scale perspective is essential for framing the scientific questions underlying these broad issues. We introduce a landscape-scale conceptual model that illustrates linkages, including material flows and animal migration, among the major ecosystem components being described in detail in a series of review papers. This model shows how linkages between ecosystem components result in remote consequences of locally applied restoration actions. The network of linkages is made more complicated by human interventions, which add components not previously a part of the landscape (e.g., salmonid hatcheries) and alter or even reverse causal relations. A landscape perspective also helps identify conceptual gaps in CALFED’s restoration strategy, such as climate change and human population growth, which should be explicitly considered in forecasts of the long-term prospects for restoration. A landscape perspective is no panacea; in particular, the effects of restoration at this scale will be difficult to detect. Nevertheless, we advocate integrating investigations of processes at nested, smaller scales as an approach for evaluating effects of individual restoration actions and of the entire program. We believe CALFED and other large restoration programs will be most successful if they are able to integrate both societal expectations and scientific study at the landscape level.