Osteoarthritis is the most common chronic musculoskeletal disorder. Although osteoarthritis is a multifactorial disease, it is known to have a significant genetic contribution. Identified genes so far, contributing to the prevalence and progression of the disease, belong to signaling pathways such as the bone morphogenetic protein and the wingless-type signaling families. These pathways are important during development and appear to be reactivated in postnatal joint homeostasis and repair. Among the most consistently associated genes, so far, are GDF5 and FRZB, which were both originally identified from a chondrogenic extract of articular cartilage. We focus on the functional aspects of these susceptibility genes and summarize recent evidence, obtained in specific animal models, for their possible roles in osteoarthritis. These data support the view that all tissues within the joint may contribute to osteoarthritis and that pathways important in skeletal development are also involved in the disease processes thereby presenting attractive therapeutic targets.