AbstractLiving cells are a complex soft material with fascinating mechanical properties. A striking feature is that, regardless of their types or states, cells exhibit a universal power-law rheological behavior which to this date still has not been captured by a single theoretical model. Here, we propose a cellular structural model that accounts for the essential mechanical responses of cell membrane, cytoplasm and cytoskeleton. We demonstrate that this model can naturally reproduce the universal power-law characteristics of cell rheology, as well as how its power-law exponent is related to cellular stiffness. More importantly, the power-law exponent can be quantitatively tuned in the range of 0.1 ~ 0.5, as found in most types of cells, by varying the stiffness or architecture of the cytoskeleton. Based on the structural characteristics, we further develop a self-similar hierarchical model that can spontaneously capture the power-law characteristics of creep compliance over time and complex modulus over frequency. The present model suggests that mechanical responses of cells may depend primarily on their generic architectural mechanism, rather than specific molecular properties.