Soft tissue stiffening is a common mechanical observation reported in foot pathologies including diabetes mellitus and gout. These material changes influence the spatial distribution of stress and affect blood flow, which is essential to nutrient entry and waste removal. An anatomically-based subject-specific foot model was developed to explore the influence of tissue stiffening on plantar pressure and internal von Mises stress at heel-strike, midstance and toe-off. This work draws on the model database developed for the Physiome project consisting of muscles, bones, soft tissue and other structures such as sensory nerves. The anisotropic structure of soft tissue was embedded in a single continuum as an efficient model for finite soft tissue deformation, and customisation methods were used to capture the unique foot profile. The model was informed by kinetics from an instrumented treadmill and kinematics from motion capture, synchronised together. Foot sole pressure predictions were evaluated against a commercial pressure platform. Key outcomes showed that internal stress can be up to 1.6 times the surface pressure with implications for internal soft tissue damage not observed at the surface. The main nerve branch stimulated during gait was the lateral plantar nerve. This subject-specific modelling framework can play an integral part in therapeutic treatments by informing assistive strategies such as mechanical noise stimulation and orthotics. Copyright © 2012 John Wiley & Sons, Ltd.