This invited presentation summarizes recent advances in the incorporation of knowledge of the geometry, tissue mechanical properties and imaging characteristics in establishing spatial correspondence between multiple images of highly deforming, soft tissue structures. Spatial correspondence is used to aid diagnosis and in the extraction of quantitative parameters for disease detection, monitoring disease progression and assessing therapeutic response. The work is illustrated through clinical examples of multi-modal imaging of the breast, assessment of small bowel motility and polyp detection in the large bowel.