Amongst experimental therapies being evaluated for myocardial infarction (MI), the field of cellular cardiomyoplasty still provokes much excitement, well into its second decade of investigation. Mesenchymal stromal/stem cells (MSCs) have held a particularly enduring place as one of the mainstays of adult-derived stem cell research in cardiovascular disease. These rare, non-hematopoietic cells are natively present throughout different postnatal tissues, most famously bone marrow, where they typically participate in perivascular stem cell niches and play key supportive and trophic roles. Their application for exogenous stem cell delivery is made attractive by their ease of isolation, proclivity for ex vivo expansion and potential for allogeneic use. There is now a remarkable wealth of in vitro and animal-based evidence attesting to the ability of MSCs to safely augment cardiac repair post-MI through pleiotropic mechanisms that continue to be delineated and in turn, optimised. However, despite such preclinical promise and the encouraging results of preliminary experience in human patients, the broader translation of MSCs to the clinical cardiovascular realm requires much more refinement to overcome fundamental limitations, not to mention rigorous validation to resolve lingering areas of uncertainty. Here we review the basic biological properties that have made MSCs so widely investigated for cardiovascular repair, discuss the preclinical evidence for their efficacy and purported mechanisms of action and consider the practicalities and evidence for their use in human patients with MI and cardiomyopathy.