Adaptive management has been adopted as the standard approach to inform the multi-billion-dollar post-Deepwater Horizon coastal restoration programs in the Gulf of Mexico. An adaptive management process can help restoration projects at multiple spatial scales-from local shorelines to entire ecosystems-by identifying critical uncertainties and guiding restoration actions away from trial and error and toward an evidence-based approach. Based on our experiences, we identify challenges that must be overcome in developing large-scale adaptive management in the Gulf of Mexico. We demonstrate how the likelihood of restoration success for eastern oyster Crassostrea virginica and other resources could increase through (1) better matching monitoring efforts and funding with on-the-ground restoration efforts and (2) coordinating similar research projects at multiple scales to share challenges, solutions, and knowledge by creating spatially and temporally replicated restoration projects to identify best restoration practices. We agree with recent U.S. National Academy of Science assessments that adaptive management offers the best framework to guide restoration in the Gulf of Mexico, but we challenge practitioners, policymakers, and managers to recognize the need for strong leadership to implement this framework as originally proposed (but rarely practiced), so that opportunities for learning are not lost.