For over five decades, fracture mechanics and damage-tolerant design have been extensively studied and used to characterize materials’ behavior under cyclic loading in structural aerospace applications. In recent years, these concepts have been adopted by other transportation sectors, including automotive and marine design. A brief overview of the history of damage tolerance and integration of fundamental materials science knowledge with fracture mechanics for structural design, fatigue life evaluations, and material development and optimization will be presented. Specifically, issues related to residual stresses, small crack growth and crack size effects, stress ratio effects, fatigue crack growth mechanisms at the material’s microstructural scale at different growth stages, critical parameters and design maps for fatigue crack growth resistance, accurate lifetime predictions, and ICME considerations will be reviewed and discussed. Examples on the application of these developments to Al and Ti alloys processed by both traditional and novel methods will also be provided.