*† In spite of the CFD revolution, significant challenges still face aerodynamicists in predicting and controlling various classes of flows. These include three-dimensional separation, boundary layer transition, interaction of separation and transition such as on reentry capsules, multi-element airfoils and wings, UAV low Reynolds number flows and high angle of attack applications. Others include multi-body flows such as those occurring in store and stage separation, “stiff” combustion reacting and unsteady flows as well as plasma aerodynamics and turbulence, to name a few. In many cases, diverse multiple scales are involved and the proper identification and treatment of associated disparate length and time scales is critical in obtaining accurate prediction and effective control. The solution of such multi-scale problems can be a hurdle to effective domain decomposition, even overset, unstructured adaptive gridding and ultimately, solution accuracy. Theoretical insights can help make proper decisions on numerical pre-processing, solution, post-processing and interpretation. Opportunities for a combined theoretical, computational and experimental approach will be discussed. These will be illustrated by examples from the author’s experience. As compared to the limited “pen and paper” theoretical methods of the 50’s, illustrations will be given of the effectiveness of combined asymptotics, similitude, group invariance, approximate physics-based modeling and numerical methods for conceptual vehicle design, flow control innovation, identification of key parameters, leveraging of computational solutions, reducing the parameter space as well as providing added insight into the basic physical processes. These will be related to tradeoffs between accuracy and response speed in typical aerospace environments.