Fatigue crack growth of long and small cracks was investigated for various Al-Si-Mg and Al-Mg cast alloys. Low residual stress was ensured during processing to concentrate on microstructural effects on crack growth. Compact tension and single edge tension specimens were fatigue crack growth tested at room temperature and stress ratio, R = 0.1. Microstructure related mechanisms were used to explain the near-threshold behaviour and crack growth response in Regions II and III for each material considering relevant microstructural features such as SDAS, grain size, and volume fraction and morphology of eutectic Si. Threshold behaviour of long cracks is attributed to closure-dependent mechanisms. In Regions II and III, the changes in crack growth mechanisms were explained through correlations between the extent of the plastic zone ahead of the crack tip and material-specific microstructural damage. Threshold behaviour of small cracks is explained through closure-independent mechanisms, specifically through the barrier effects of controlling microstructural characteristics specific to each material. Recommendations for integrating materials knowledge in structural design for fatigue performance are given.