Through element substitution in Cu2ZnSnS4, a class of kesterite-structured I2–II–IV–VI4 semiconductors can be designed as novel functional materials. Using the first-principles calculations, we show that this element-substitution design is thermodynamically limited, that is, although I2–II–IV–VI4 with I = Cu, Ag, II = Zn, Cd, Hg, IV = Si, Ge, Sn, and VI = S, Se, Te are stable quaternary compounds, those with II = Mg, Ca, Sr, Ba, IV =Ti, Zr, Hf, and VI = O are unstable against the phase-separation into the competing binary and ternary compounds. Three main phase-separation pathways are revealed. In general, we show that if the secondary II–VI or I2–IV–VI3 phases prefer to have nontetrahedral structures, then the I2–II–IV–VI4 semiconductors tend to phase separate. This finding can be used as a guideline for future design of new quaternary semiconductors.