Multipotential mesenchymal stem cells (MSCs) are able to differentiate along several known lineages and have been shown to be efficacious for in vivo wound repair. The growth and differentiation of MSCs are known to be tightly regulated via interactions with specific extracellular mediators. Recent studies have shown that Wnts and their downstream signaling pathways play an important role in the self-renewal and differentiation of MSCs. Indeed altered bone-mass is known to result from mutations in LRP5, a Wnt co-receptor, that suggests Wnt plays an important signaling role during bone formation, possibly involving MSCs. This review outlines the current understanding of the distinct Wnt intracellular pathways including both canonical beta-catenin/TCF(LEF1) signaling and non-canonical cascades mediated by JNK, PKC, Ca(2+) or Rho, and how they are involved in the regulation of MSC proliferation and differentiation. We also discuss the coordination between different Wnt signaling cascades to precisely control MSC cell fate decisions, and we dissect the functional cross-talk of Wnt signaling that is known to occur with other growth factor signaling pathways.