Many unicellular organisms take their outer proteinaceous and lipidic membranes or carbonhydrate-rich cell walls as a template for biomineralization to synthesize a thin mineral layer as a functional covering. In nature most cells cannot be mineralized spontaneously in the normal states. Inspired by nature, we develop cytocompatible methods for cells encapsulated inside a mineral shell, called “cellular shellization.” Using Layer-by-Layer (LbL) assembly, the precipitation of calcium minerals can be induced on the yeast cell surfaces. The effects of different synthetic polyelectrolytes on the calcifications of yeast, such as interfacial energy, zeta-potential, introduction time, and the affinity of mineral phase on the yeast cell surface have been studied by using constant composition method (CC) systemically and quantitatively. The results demonstrate that the effective adsorption of polyelectrolytes with carboxyl or sulfonate-rich groups on the yeast can enhance mineralization abilities of yeast cells readily, and the factor of interfacial energy plays a key role in the superficial mineralization of the cells. Furthermore, the influences of ion concentrations, as well as titration rates on the formation of inorganic shell, have also been examined. It is found that the biomimetic shell formation on the cell can also be achieved by using an appropriate selection of titration conditions rather than the pretreatment of LbL. Thus, the control of cellular biomineralization can become more feasible. In this study, we show that adjusting the interfacial energy is the key to cellular mineralization and suggest that these biomineralization treatments of single-cell may be applied as a potential and universal approach for cell-based sensing and therapy. Biotechnol. Bioeng. 2014;111: 386–395. © 2013 Wiley Periodicals, Inc.