Life is a dynamic event, and cells represent its smallest structural and functional units that can exist on their own. Cells and the surrounding extra cellular matrix are in a constant flux of change imposed by each other. The aim of this chapter is to look into the complex interplay of physical and chemical factors imposed on cells, in particular mesenchymal stem cells (MSCs), via their microenvironment and how such factors influence MSCs response. Some of the defined and independently varied factors such as surface chemistry, modulus and topography are reviewed in this chapter, with a focus on cell physicochemical memory formation. Acknowledging the importance of mechanical and chemical stimuli experienced by cells and their polarity, while investigating the interdependent relationship between them, will not only help develop more fitting culture systems, for instance to maintain stem cell multipotency, but advance the understanding of how such extracellular stimuli are understood and acted upon by cells during their lifetime.