In this paper, we present a theoretical modeling framework for pinhole growth in a polymer-electrolyte-fuel-cell membrane due to environmentally-driven cyclic loads. The focus is to develop a quantitative understanding and prediction of fuel-crossover and cell-performance data, and to explore approaches for membrane lifetime estimations due to humidity variations and associated mechanical stresses. A mechanistic approach based on void-growth in solid mechanics is employed for the cyclic, or fatigue, response of the membrane that consists of multi-parameter submodels for various phenomena related to the growth of a pinhole due to membrane deformation. To consider the critical role of swelling (hydration) and plasticity, expressions for the membrane's hydration-dependent nonlinear elastic-plastic constitutive response are developed based on measured material properties and implemented into the model. Effects of loading (hydration) conditions, model parameters, and membrane material properties on the resulting mechanical response and lifetime are investigated. Lastly, by correlating the pinhole area to crossover in the membrane, model predictions are compared with experimental accelerated-stress-test (AST) data. The results support the combined degradation mechanisms that mechanical effects, while not resulting in sudden failure due to humidity cycling, accelerate chemical degradation during a combined mechanical/chemical AST test.