Obesity and degenerative joint disease (osteoarthritis, OA) are two multifactorial pathologies that are becoming major medical issues with the aging of the world population. The relationship of OA with obesity is complex, involving both biomechanical and metabolic links. Dysregulated production of adipose tissue-derived inflammatory mediators, hyperlipidemia, and increased systemic oxidative stress are conditions frequently associated with obesity that may favor joint degeneration. In addition, it is remarkable that many regulatory factors have been implicated in the development, maintenance and function of both adipose tissues and cartilage and other articular joint tissues. Disturbances in these factors may underlie additional links between obesity and OA. In this review, molecular players at the intersection of adipose tissue and joint cell biology - including differentiation signals and transcription factors, extracellular matrix components and remodelers, joint cell- and adipose tissue cell-derived mediators (cytokines, adipokines), hypoxia inducible transcription factors, lipids, advanced glycation end products and miRNAs - are reviewed, with emphasis on their dysregulation in obesity and OA. Knowledge of these factors may illuminate a novel, adipocentric avenue for the pathogenesis and therapy of OA and other joint diseases.