Osteoarthritis occurs when synovial joints fail. Drugs that alter the course of this disease, rather than simply alleviate symptoms, are in clinical trials, but none have been approved yet in the United States or the European Union. Johnson et al. describe the discovery and characterization of a small molecule, kartogenin, that improves joint function and promotes the regeneration of cartilage in vivo in two rodent models of chronic and acute joint injury. In vitro experiments indicated that kartogenin induces the differentiation of mesenchymal stem cells into cartilage cells (chondrocytes) and protects existing chondrocytes under pathophysiological conditions. The authors found that kartogenin binds filamin A, a protein that crosslinks actin filaments, through which it regulates the nuclear localization of a transcription factor complex of CBFβ and RUNX2. Knockdown of either CBFβ or RUNX2 with short-hairpin RNAs blocked the effect of kartogenin on cellular differentiation. Kartogenin is the first drug reported to target filamin A and as such may complement other osteoarthritis drugs under development. (Science published online, doi:10.1126/science.1215157, 5 April 2012)