Research into mesenchymal stromal/stem cells (MSCs) has been particularly exciting in the past five years. Our understanding of mechanisms of MSC-mediated tissue regeneration has undergone considerable evolution. Recent investigation of the primary in situ counterpart of cultured MSCs has led to fresh insights into MSC physiology and its role in the immune system. At the same time, the clinical application of MSCs continues to increase markedly. Taken together, a reappraisal of the definition of MSCs, a review of current research directions, and a reassessment of the approach to clinical investigation are timely and prudent.