The Committee on Modeling and Simulation Enhancements for 21st Century Manufacturing and Acquisition was formed by the NRC in response to a request from the Defense Modeling and Simulation Office (DMSO) of DOD. The committee was asked to (1) investigate next-generation evolutionary and revolutionary M&S capabilities that will support enhanced defense systems acquisition; (2) identify specific emerging design, testing, and manufacturing process technologies that can be enabled by advanced M&S capabilities; (3) relate these emerging technologies to long-term DOD requirements; (4) assess ongoing efforts to develop advanced M&S capabilities and identify gaps that must be filled to make the emerging technologies a reality; (5) identify lessons learned from industry; and (6) recommend specific government actions to expedite development and to enable maximum DOD and U.S. commercial benefit from these capabilities. To complete its task, the committee identified relevant trends and their impact on defense acquisition needs; current use and support for use of M&S within DOD; lessons learned from commercial manufacturing; three cross-cutting and especially challenging uses of M&S technologies; and the areas in which basic research is needed in M&S in order to achieve the desired goals for manufacturing and defense acquisition.