The fatigue threshold of large cracks is known to show substantial variations due to microstructural variability in structural alloys. The ⌬K th variations are dependent on the stress ratio (R); they are extremely large at low R ratios, e.g., R Ͻ 0.5, but are drastically reduced at high R ratios (R Ͼ 0.8). The origins of these large variations due to intrinsic and extrinsic mechanisms are examined by theoretical analyses. First, an intrinsic fatigue crack growth (FCG) threshold model is developed for structural alloys by considering the cyclic slip process at the crack tip. Second, the effects of extrinsic mechanisms such as residual plastic stretch, crack deflection, fracture-surface roughness, and oxide wedging are considered both individually and concurrently in order to delineate their relative contributions to threshold variability. The theoretical results indicate that the intrinsic threshold depends on the elastic properties, magnitude of the Burgers vector, yield stress, and Taylor factor (i.e., texture), but is independent of the R ratio or the maximum applied stress intensity factor, K max . The large variability of ⌬K th at low R ratios and their corresponding dependence on K max appear to arise from various crack closure mechanisms. Applications of the threshold models to structural alloys show good agreement between theory and experimental data from the literature for steels, Ti, Al, Ni, Cu, Nb, and Mo alloys.