Articular cartilage injuries and degenerative joint diseases are responsible for progressive pain and disability in millions of people worldwide, yet there is currently no treatment available to restore full joint functionality. As the tissue functions under mechanical load, an understanding of the physiologic or pathologic effects of biomechanical factors on cartilage physiology is of particular interest. Here, we highlight studies that have measured cartilage deformation at scales ranging from the macroscale to the microscale, as well as the responses of the resident cartilage cells, chondrocytes, to mechanical loading using in vitro and in vivo approaches. From these studies, it is clear that there exists a complex interplay among mechanical, inflammatory, and biochemical factors that can either support or inhibit cartilage matrix homeostasis under normal or pathologic conditions. Understanding these interactions is an important step toward developing tissue engineering approaches and therapeutic interventions for cartilage pathologies, such as osteoarthritis.