Mesenchymal stromal cells (MSC) are multipotent stem cells that can be derived from several different tissues, including bone marrow. In preclinical studies, MSC have been found to improve outcome after stroke with a time window measured in days-weeks, in a manner robust across species, delivery route, allogenicity, and dose. These effects are achieved via multiple mechanisms in parallel, including paracrine elaboration of neurotrophins and remote immunomodulation. Human studies support the safety of MSC administration after stroke. Future trials can be designed with attention to key issues reviewed herein, including choices during MSC manufacture, and principles of brain repair.