Mesenchymal stromal/stem cells (MSCs) are a small population of stromal cells present in most adult connective tissues, such as bone marrow, fat tissue, and umbilical cord blood. MSCs are maintained in a relative state of quiescence in vivo but, in response to a variety of physiological and pathological stimuli, are capable of proliferating then differentiating into osteoblasts, chondrocytes, adipocytes, or other mesoderm-type lineages like smooth muscle cells (SMCs) and cardiomyocytes. Multiple signaling networks orchestrate MSCs differentiating into functional mesenchymal lineages. Among these, transforming growth factor-beta 1 (TGF-beta 1) has emerged as a key player. Hence, we summarize the effects of TGF-beta 1 on differentiation of MSCs toward different lineages. TGF-beta 1 can induce either chondrogenic or SMC differentiation of MSCs in vitro. However, it requires cell-cell and cell-matrix interactions, similar to development of these tissues in vivo. The effect of TGF-beta 1-regulated osteogenic differentiation of MSCs in vitro depends on the specific culture conditions involved. TGF-beta 1 inhibits adipogenic differentiation of MSCs in monolayer culture. Using this information, we may optimize the culture conditions to differentiate MSCs into desired lineages. (C) 2011 Elsevier Inc.