An increased recruitment of new preadipocytes from mesenchymal stem cell (MSC) sources to form adipocytes and deposit adipose tissue is one of the features of obesity. In this chapter, the role of mechanical extracellular environments in directing MSC adipogenic commitment and differentiation will be reviewed. It was recently highlighted that adipose cells and their precursor cells, including MSCs, are exposed in vivo to complex mechanical stimulations. Further, studies proposed that adipose cells are ‘mechanically sensitive and responsive’, which is a characteristic of traditionally well-established mechanoresponsive cells such as osteoblasts, chondrocytes, myoblasts, etc. While it is still in the early stage of ‘adipocyte mechanotransduction’ research, this chapter will review the data reported on the control of MSC fate decision to adipogenesis via utilizing mechanical cell stimulations (stretch, compression, fluid flow) and also via static mechanophysical signals from the cell culture substrate. Also, comparison of MSC adipogenesis with the osteogenesis, as attempted in many of these studies, will be reviewed. Determining extracellular mechanophysical conditions optimal to inhibit the MSC adipogenesis and revealing underlying molecular mechanistic pathways may significantly advance the strategy to deal with obesity.