Additive manufacturing (AM) of metal components is a growing advanced manufacturing paradigm that promises unparalleled flexibility in the production of parts with complex geometries. However, the extreme processing conditions create inhomogeneous materials that can include intense localized compositional gradients, elongated microstructures, pronounced crystallographic texture, highly anisotropic local and macroscopic stresses, and non-equilibrium phases. Typically, such as-built parts require substantial post-build thermal and thermo-mechanical processing to achieve the consistent, predictable mechanical properties required for commercial applications. Unfortunately, traditional heat treatments rely upon consistent starting microstructures that are radically different from many AM-built materials. We are developing rational methodologies for optimizing the build and post build processing steps using a combination of multicomponent computational thermodynamic and kinetic microstructural evolution simulations, finite element modeling, and world-leading stress and microstructure characterization methods using synchrotron X-rays, neutrons, and lab-based measurements. Results will be presented for Inconel 625 and 17-4 steel test cases.