Functional genomics is a challenging new way to address a complex disease like osteoarthritis on a molecular level. Despite osteoarthritis being ultimately a biochemical problem, mainly characterized by an imbalanced cartilage matrix turnover, a deeper understanding of molecular events within the tissue cells (i.e., the chondrocytes) will provide not only a better understanding of pathogenetic mechanisms but also new diagnostic markers and cellular targets for therapeutic intervention. This innovative technology represents a challenging approach complementing (not replacing) classical research in previously described and new disease-relevant genes: large-scale functional genomics will open up new areas of so far unrecognized molecular networks. This will include as yet unidentified players in the anabolic–catabolic balance of matrix turnover of articular cartilage as well as disease-relevant intracellular signaling cascades so far hardly investigated in articular chondrocytes. However, care must be taken not to over or misinterpret results and some major challenges must be overcome in order to properly utilize the potential of this technology in the field of osteoarthritis.