The basic helix-loop-helix transcription factor Twist-1 is known to mediate mesodermal tissue development and contributes to correct patterning of the human skeleton. Enforced expression of Twist-1 in human MSC in vitro increased their proliferative potential and adipogenic differentiation capacity while simultaneously reducing their osteogenic/chondrogenic differentiation capacity. Furthermore, we showed that Twist-1 activated the Wnt signalling pathway through direct induction of Wnt2 and Wnt2b expression while repressing BMP-4 and TGFb-1 expression. The present study also investigated the role of Twist-1 in postnatal bone fracture healing. The fracture studies were performed by inducing an internally stabilised femoral fracture in heterozygous Twist-1+/- mice and wild type littermate controls. Analysis of the incidence of clonogenic osteoprogenitors (CFU-F), mechanical properties of the bone, µCT and histology demonstrated enhanced fracture healing in heterozygous mice when compared to wild type littermate controls. Infiltration of the fracture site by a more mature population of mesenchymal cells in heterozygous animals at one week enabled earlier callus formation by a pre-committed population of osteogenic cells. By comparing fractured to contralateral limbs at eight weeks post fracture it was evident that relative differences were much smaller on all levels of analysis in heterozygous animals compared to wild type littermate controls indicating more comprehensive healing and remodelling in the heterozygous population. These findings implicate Twist-1 as a mediator of MSC self-renewal and lineage commitment in postnatal skeletal tissue and bone repair.