We examine catalyst layer (CL) microstructural sensitivity to polymer electrolyte fuel cell (PEFC) performance by generalizing the agglomerate modeling and optimization framework presented by Jain et al. [Electrochem. Solid-State Lett., 11, B193 (2008)]. We first investigate the shape sensitivity of agglomerates on intra-and interagglomerate transport processes via effectiveness factors and effective transport models. We also examine the agglomerate size sensitivity by generating self-similar CL structures and controlled polydisperse systems possessing a particle size distribution. Furthermore, via examining multizone agglomerate, we introduce nonuniformly distributed sites for electrochemical reaction called the triple phase boundaries. Our results demonstrate large sensitivities in simulation and optimization results to different shapes and sizes of CL structures. (C) 2010 The Electrochemical Society. [DOI:10.1149/1.3454725] All rights reserved.