The development of the next generation of multi-domain unmanned semi and fully autonomous C4ISR systems involves a multitude of security concerns and interoperability challenges. Conceptual solutions to capability shortfalls and gaps can be identified through Concept Development and Experimentation (CD and E) cycles. Modelling and Simulation (M and S) is a key tool in supporting unmanned autonomous systems (UAxS) CD and E activities and addressing associated security challenges. This paper serves to illustrate the application of M and S to UAxS development and highlight initiatives made by the North Atlantic Treaty Organization (NATO) M and S Centre of Excellence (CoE) to facilitate interoperability. The NATO M and S CoE collaborates with other NATO and Nations bodies in order to develop UAxS projects such as the Allied Command for Transformation Counter Unmanned Autonomous Systems (CUAxS) project or the work of Science and Technology Organization (STO) panels. Some initiatives, such as Simulated Interactive Robotics Initiative (SIRI) made the baseline for further developments and to study emerging technologies in M and S and robotics fields. Artificial Intelligence algorithm modelling, Robot Operating Systems (ROS), network operations, cyber security, interoperable languages and related data models are some of the main aspects considered in this paper. In particular, the implementation of interoperable languages like C-BML and NIEM MilOps are discussed in relation to a Command and Control - Simulation Interoperability (C2SIM) paradigm. All these technologies are used to build a conceptual architecture to support UAxS CD and E.In addition, other projects that the NATO M and S CoE is involved in, such as the NATO Urbanization Project could provide credible future operational environments and benefit UAxS project development, as dual application of UAxS technology in large urbanized areas.In conclusion, this paper contains a detailed overview regarding how applying Modelling and Simulation to support CD and E activities is a valid approach to develop and validate future capabilities requirements in general and next generation UAxS.