The extracellular matrix of articular cartilage is the primary target of osteoarthritic cartilage degradation. However, cartilage cells have a pivotal role during osteoarthritis, as they are mainly responsible for the anabolic-catabolic balance required for matrix maintenance and tissue function. In addition to the severe changes in the extracellular matrix, the cells also display abnormalities during osteoarthritic cartilage degeneration, such as inappropriate activation of anabolic and catabolic activities, and alterations in cell number through processes like proliferation and (apoptotic) cell death. The cells are exposed to additional stimuli such as nonphysiologic loading conditions and byproducts of matrix destruction, as well as abnormal levels of cytokines and growth factors. This exposure can lead to a structured cellular response pattern that may be either beneficial or detrimental to the cartilage tissue. Potentially even more problematic for preserving tissue homeostasis, neighboring osteoarthritic chondrocytes display strong heterogeneity in their phenotype, gene expression patterns, and cellular responses. As the disease progresses, osteoarthritic chondrocytes can no longer maintain tissue integrity. Evidence suggests that cell aging is important in the pathogenesis of osteoarthritis. Thus, anti-aging strategies might complement existing therapeutic targets related to anabolism, catabolism, inflammation, and apoptosis-processes that are integral to the pathogenesis of osteoarthritis.