Knee osteoarthritis is a disease that can be initiated along multiple pathways that ultimately leads to pain, loss of function and breakdown of the articular cartilage. While the various pathways have biological and structural elements, the mechanical pathways play a critical role in the development of the disease. The forces and motions occurring during ambulation provide mechanical signals sensed at the scale of the cell that are critical to healthy joint homeostasis. As such, ambulatory changes associated with aging, obesity, or joint injury that occur prior to the development of symptoms of OA can ultimately lead to clinical OA. Conversely, inter-scale signaling (e.g., pain) generated by biological changes in the early stages of OA can produce adaptive ambulatory changes that can modify the rate of OA progression. Thus, the nature of the physical and clinical response to the mechanical signals that occur during ambulation is critical to understanding the etiology of osteoarthritis.