Friction stir welding (FSW) is a relatively new solid-state joining technique, which provides good weld properties and behavior, even without the need of post-weld heat treatment. Understanding and predicting microstructure evolution and mechanical properties in FSW is critical for high-integrity structural design and material-process optimization. Four aluminum alloys (wrought 6061 and cast A356, 319, and A390) have been investigated in both as-fabricated and pre-weld heat treated conditions using various combinations of rotation and traverse speeds. An original thermo-mechanical model was created to predict the thermal history, stress distributions, deformation rates, and velocity fields in FSW. Further, a methodology for evaluating and indexing weld quality was also developed and used to establish optimized processing domains for each material. Resulting microstructures, hardness/micro-hardness, and tensile properties were systematically evaluated and mechanistically correlated to morphological changes in grain structures, characteristic phases, and strengthening precipitates using both experimental characterization and thermo-mechanical model predictions.