Improving our understanding of the role that microstructure has on the performance and durability of polymer electrolyte fuel cell (PEFC) cathodes is critical to advancing this technology. Modeling is an important tool in interpreting imaging and experimental characterization of microstructure effects because it allows us to quantify the impact that specific microstructure characteristics have and also allows us to visualize processes and quantities that are otherwise inaccessible in the physical system. Various continuum-level and volume-averaging approaches are available to incorporate idealized microstructural effects, but they unfortunately are generally limited to highly idealized geometries and decoupled and simplified transport and reaction models. Herein, we will present recent advances in directly modeling transport, reaction, and degradation mechanisms in catalyst layers where a spatially-resolved multi-dimensional representation of the microstructure is used to capture the impact of anisotropic and heterogeneous features. In these works, the microstructure geometry is often generated through 3D computed tomography (CT), stochastic reconstruction, or a combination thereof. For example, high resolution scanning transmission electron microscope CT (STEM-CT) images can be combined with X-ray nano-CT images to stochastically reconstruct the catalyst layer microstructure with both electrode and catalyst length scales resolved. In addition, correlative methods of incorporating different imaging modalities can be used to resolve the properties and distribution of multiple material phases, including spatial ionomer loading heterogeneity in the cathode. In addition to advances in the field, this work will highlight progress in our group in applying microstructural modeling to both Pt/Pt-alloy and Pt group metal-free (PGM-free) catalyst cathodes. The modeling domains we consider in our work span from Pt particles embedded in high surface area carbon supports to transport and reaction across the electrode thickness. The modeling results range from characterizing microstructural effects on the effective transport properties for the bulk electrode to particle-scale modeling of catalyst metal dissolution and redistribution.