Regional-scale restoration is a tool of growing importance in environmental management, and the number, scope, and complexity of restoration programs is increasing. Although the importance of natural science to the success of such projects generally is recognized, the actual use of natural science in these programs rarely has been evaluated. We used techniques of program evaluation to examine the use of natural science in six American and three Western European regional-scale restoration programs. Our results suggest that ensuring the technical rigor and directed application of the science is important to program development and delivery. However, the influence of science may be constrained if strategies for its integration into the broader program are lacking. Consequently, the influence of natural science in restoration programs is greatest when formal mechanisms exist for incorporating science into programs, for example, via a framework for integration of science and policy. Our evaluation proposes a model that can be used to enhance the influence of natural science in regional-scale restoration programs in the United States and elsewhere.