We demonstrated a convincing case that using the free energy concept to rationalize cell-material interactions is not a fantasy. The key mechanism by which substrate stiffness influences cell morphology is the energy tradeoff between the stabilizing influence of the cell-substrate interfacial adhesive energy and the destabilizing influence of the total elastic energies in the system, the interchange between forms of energy governing adherent cell morphology. Thus, we presented for the first time that intrinsic cell modulus can be measured noninvasively from global changes in cell morphology in response to changes in substrate stiffness. Our methodology to measure cell modulus would significantly impact research communities that are increasingly recognizing cell stiffness as a means to understand its relationship with cell properties and to alter cell phenotype in various cellular processes. Also, the new knowledge of intrinsic cell modulus and insight into cell-material interactions are critical for designing tissue engineering scaffolds with an appropriate stiffness to modulate cell phenotype and/or differentiation in regenerative medicine applications. Live cells are self-regulating systems that can select their own response to a given external perturbation or internal force. Our work suggested that this response, though biological in nature, follows the laws of the energy interchange in order to achieve the self-regulated behavior. This knowledge could be extended to yield novel implications for thermodynamics studies into a cell's innate self-regulating activity and new thoughts regarding energetic processes at the subcellular level.