Acute renal failure (ARF; acute kidney injury-according to the more recent classification) is emerging as a public health problem. Despite major advances in supportive therapy, the mortality and morbidity among patients remain dismally high. In the attempt to yield innovative interventions fostering the limited capability of regeneration of the kidney, several studies have tested stem cell-based technology mainly employing mesenchymal stem cells (MSC) of different origins. The results of this approach provide the exciting prospect of a powerful treatment to repair acutely damaged organs by virtue of the unique MSC tropism for the damaged tissue, as well as their paracrine action. In the present review, we discuss the mechanisms underlying the regenerative processes triggered by MSC therapy in preclinical models of ARF by analysing modalities of cell-to-cell communication through the release of soluble factors and microvesicles/exosomes by MSC into the damaged renal tissue. Key receptors involved in MSC homing, engraftment and survival at the sites of injury are also elucidated. A translation of basic discoveries of MSC biology into effective care is still limited to the preliminary data of a phase I clinical trial, and further studies are needed to definitively assess the efficacy of MSC-based therapy in humans.