This paper presents the positions of seven international experts regarding current and future grand challenges for modeling and simulation (M&S) supporting the defense and security domain. Topics addressed include new interoperability issues, real-time analysis challenges, evolving military and training exercises, the future role and importance of Operations Research and M&S, modeling human teams and cultural behavior challenges, how to support successful co-evolving of research and academic programs, and the implications of enterprise postures and operational concepts of future M&S. In summary, all contributions focus on a particular facet that in summary help to understand the conceptual, technical, and organizational challenges we are currently facing.