Pressure ulcers are areas of soft tissue breakdown that result from sustained mechanical loading of the skin and underlying tissues; they can affect the quality of life of many individuals. Despite considerable efforts to prevent pressure ulcers, data on prevalence are unacceptably high. This can at least partly be attributed to limited knowledge of the etiology of the clinical condition and the fact that identification and prevention of pressure ulcers mainly focus on skin tissue, even though the underlying muscle tissue may be more susceptible to mechanical loading. The present article proposes a new, hierarchical research approach to obtain improved insights into the basic pathways whereby mechanical loading leads to soft tissue breakdown. This approach investigates the relationships between (1) global mechanical loading at skin level, (2) the resulting local internal mechanical conditions within the soft tissue layers extending from skin to muscle tissue, and (3) the pathophysiologic response to loading. The latter response should be assessed from the various functional tissue units involved in soft-tissue breakdown-the cells, the interstitial space, and blood and lymph vessels. We predict that the proposed strategy will provide new fundamental knowledge about the etiology of pressure ulcers that can serve as a sound basis for effective clinical identification and prevention.