Bone and cartilage disorders affect over half of all adults over the age of 50 and their prevalence is increasing. Osteoporosis and osteoarthritis are the commonest bone and joint disorders. Current treatments for osteoporosis reduce fracture risk by only 50% and there are concerns regarding side effects and long-term safety. Patients with osteoarthritis are asymptomatic in the early stages of disease, develop problems only after significant cartilage erosion has occurred and no drugs are available to prevent or delay disease progression. Thus, there is urgent need to advance understanding and define new molecular pathways that facilitate development of new treatment options. Susceptibility of osteoporosis and osteoarthritis is genetically determined but <5% of this heritability is accounted for by known genetic variation. To discover the function of all known genes, the International Knockout Mouse Consortium is undertaking large scale gene targeting to disrupt each of the >20,000 protein-coding genes in C57BL/6 mice.  We hypothesise that bone- and joint-specific extreme phenotype screens in knockout mice will (i) identify novel pathways regulating normal bone and cartilage development, maintenance and resilience; (ii) uncover new genetic determinants of disease; and (iii) provide in vivo models to elucidate their molecular basis and investigate novel treatments. To address these hypotheses, we have adopted multi-disciplinary high-throughput screening approaches to identify knockout mice with outlier bone and joint phenotypes and thus identify new genes and regulatory networks that underpin skeletal development, maintenance, integrity and function.