Mechanism-based models for the evolution of defects during the thermomechanical processing of aerospace titanium- and nickel-based alloys are reviewed. These defects include those comprising microstructural/metal-flow irregularities and those that are damage related (i.e., cracks and cavities). The development of undesirable/nonuniform microstructures and cavities during the mill processing of alpha/beta titanium alloys is addressed first. Relatively simple, diffusion-based models of spheroidization and coarsening are applied to quantify the propensity for microstructure nonuniformities. Similarly, first-order micromechanical models have been formulated to estimate the effect of local crystallographic texture on nonuniform flow, the generation of triaxial stresses, and cavity growth/closure in alpha/beta titanium alloys with a colony-alpha microstructure. The occurrence of nonuniform grain structures (and so-called ALA, or “as large as,” grains) in cast, wrought, and powder-metallurgy superalloys is also discussed. A physics-based model to treat the topology of recrystallization and the evolution of ALA grains in such materials is proposed.