AbstractCell volume regulation, as one of the fundamental homeostasis of the cell, is associated with many cellular behaviors and functions. With the increased studies on the effect of environmental mechanical cues on cell volume regulation, the relationship between cell volume regulation and mechanotransduction becomes more and more clear. In this paper, we review the mechanisms and hypotheses by which cell maintains its volume homeostasis both in vivo and in constructed cell mechanical microenvironment (CMM) in vitro. We discuss how the growth‐division regulation maintains the volume homeostasis of cells in the cell cycle and how the cell cortex/membrane tension mediates the effect of CMM (i.e., osmotic pressure, matrix stiffness, and mechanical force) on cell volume regulation. We also highlight the roles of cell volume as a perfect integrator of the downstream signals of mechanotransduction from different aspects of CMM and an effective indicator for the mechanical condition that cell confronts. This interdisciplinary perspective can provide new insight into biomechanics and may shed light on bioengineering and pathological research work. We hope this review can facilitate future studies on the investigation of the role of cell volume in mechanotransduction.