The Automotive Partnership of Canada (APC) project on Next-Gen Heavy Duty Fuel Cell Buses is a government supported three-year project dedicated to research and product development of next generation heavy duty fuel cell buses in Canada (www.apc-hdfc.ca). The project represents a collaborative effort between Ballard Power Systems, Simon Fraser University and University of Victoria in British Columbia, Canada. The overarching objective is fundamental understanding of membrane degradation mechanisms, degradation rates, and failure modes under drive cycles and conditions that are typical for heavy duty vehicle operation. The aim is to help develop next generation fuel cell technology that is equivalent to or surpasses incumbent diesel engines in terms of durability and reliability, while reducing capital and warranty costs.In order to develop new durable membrane technologies and devise mitigation strategies to reach desired membrane lifetime, empirical and physical models need to be developed and employed. In this context, understanding the relationship between operation mode and membrane degradation under heavy duty fuel cell conditions is of vital importance. Apart from mechanical degradation such as thinning and pinhole formations, chemical and electrochemical degradation could also take place in perfluorosulfonated acid (PFSA) ionomer membranes. Due to complexity of the underlying processes, degradation mechanisms and their dependence on relevant operating conditions are not generally well established.We present results from an extensive effort that integrates multi-scale, multi-disciplinary modeling with large–scale accelerated degradation testing data. Results are analysed in view of the relative importance of various membrane degradation mechanisms via various chemical and mechanical processes. The versatile multi-scale modeling framework includes structure formation at molecular/meso-scales, water sorption characteristics, kinetics, as well as continuum modelling of chemical and mechanical degradation processes.