Acute kidney injury (AKI) is a common clinical complication, associated with poor outcomes and the development of chronic kidney disease. Despite major advances in the understanding of its pathophysiology, available therapies for AKI are only supportive; therefore, adequate functional recovery from AKI must predominantly rely on the kidney’s own reparative ability. Mesenchymal stem cells (MSCs) have multipotent and self-renewing properties and can differentiate into cells of the mesodermal lineage. Their potential role in endogenous repair and cell-based therapies for acute kidney injury (AKI) is under intensive investigation. This assay summarizes the current knowledge and helps to identify the gaps in our understanding of MSC features and the factors they release that protect against kidney injury through paracrine and endocrine effects, including mitogenic, antiapoptotic, anti-inflammatory, and angiogenic influences, the mechanisms of homing and engraftment to sites of inflammation; and further elucidate the immune-modulatory effect of MSC and their ability to alter macrophage phenotype in a setting of kidney damage and repair.