The four topical articles of the Tidal Wetlands Restoration Series summarized and synthesized much of what is known about tidal wetlands and tidal wetland restoration in the San Francisco Estuary (hereafter “Estuary”). Despite a substantial amount of available information, major uncertainties remain. A major uncertainty with regard to fishes is the net benefit of restored tidal wetlands relative to other habitats for native fishes in different regions of the Estuary given the presence of numerous invasive alien species. With regard to organic carbon, a major uncertainty is the net benefit of land use change given uncertainty about the quantity and quality of different forms of organic carbon resulting from different land uses. A major challenge is determining the flux of organic carbon from open systems like tidal wetlands. Converting present land uses to tidal wetlands will almost certainly result in increased methylation of mercury at the local scale with associated accumulation of mercury within local food webs. However, it is unclear if such local accumulation is of concern for fish, wildlife or humans at the local scale or if cumulative effects at the regional scale will emerge. Based on available information it is expected that restored tidal wetlands will remain stable once constructed; however, there is uncertainty associated with the available data regarding the balance of sediment accretion, sea-level rise, and sediment erosion. There is also uncertainty regarding the cumulative effect of many tidal restoration projects on sediment supply. The conclusions of the articles highlight the need to adopt a regional and multidisciplinary approach to tidal wetland restoration in the Estuary. The Science Program of the CALFED effort provides an appropriate venue for addressing these issues.