The effects of mechanical stress on lithium-ion battery life are investigated by monitoring the stack pressure and capacity of constrained commercial lithium-ion pouch cells during cycling. Stack stress is found to be a dynamic quantity, fluctuating with charge/discharge and gradually increasing irreversibly over long times with cycling. Variations in initial stack pressure, an important controllable manufacturing parameter, are shown to produce different stress evolution characteristics over the lifetime of the cells. Cells manufactured with higher levels of stack pressure are found to exhibit shorter cycle lives, although small amounts of stack pressure lead to increased capacity retention over unconstrained cells. Postmortem analysis of these cells suggests a coupling between mechanics and electrochemistry in which higher levels of mechanical stress lead to higher rates of chemical degradation, while layer delamination is responsible for the capacity fade in unconstrained cells. Localized separator deformation resulting in nonuniform lithium transport is also observed in all cells.