Mesenchymal stromal cells found within bone marrow, fat, and other tissues are a population of cells with the potential to mediate therapeutic outcomes based on differentiation into multiple cell lineages or through paracrine-mediated mechanisms that influence angiogenesis, apoptosis, or immune response. Currently, mesenchymal stromal cells are being widely investigated for numerous tissue engineering and regenerative medicine applications. Appropriate animal models will be crucial to the development and evaluation of regenerative medicine-based treatments and eventual cures for debilitating diseases. Here, we summarize the ongoing research focused on studying the biological and therapeutic potential of mesenchymal stromal cells in large-animal models.