The fatigue resistance of metallic structures is inherently random due to environmental and boundary conditions, and microstructural geometry, including discontinuities, and material properties. A new methodology for fatigue life prediction is under development to account for these sources of randomness. One essential aspect of the methodology is the ability to perform truly multiscale simulations: simulations that directly link the boundary conditions on the structural length scale to the damage mechanisms of the microstructural length scale. This presentation compares and contrasts two multiscale methods suitable for fatigue life prediction. The first is a brute force method employing the widely-used multipoint constraint technique which couples a finite element model of the microstructure within the finite element model of the structural component. The second is a more subtle, modified multi-grid method which alternates analyses between the two finite element models while representing the evolving microstructural damage. Examples and comparisons are made for several geometries and preliminary validation is achieved with comparison to experimental tests conducted by the Northrop Grumman Corporation on a wing-panel structural geometry.