The growth/differentiation factors (GDFs) are a subfamily of the highly conserved group of bone morphogenetic protein (BMP) signaling molecules known to play a diverse set of roles in the skeletal system. GDFs 5, 6, and 7 in particular have been grouped together on the basis of the high degree of amino acid sequence homology in the C-terminal signaling region of these proteins. The existence of several naturally occurring and engineered mouse models with functional null mutations in these GDFs has led to a variety of investigations into the effects of GDF deficiency on skeletal tissues and processes. The best characterized of these models to date is the GDF-5-deficient brachypod (bp) mouse. In this paper, a comprehensive review of the studies performed on the bp mouse is provided in an effort to elucidate implications for potential therapeutic bioengineering applications using GDF-5. On the basis of the available evidence to date, GDF-5 may hold promise as a possible therapeutic agent for applications involving tendon/ligament repair as well as perhaps intervertebral disk degeneration, cartilage repair, and bone augmentation, although further detailed interventional studies will be required to investigate these potential applications.