Liebig’s law of the minimum (LLM) is often used to interpret empirical biological growth data and model multiple substrates co-limited growth. However, its mechanistic foundation is rarely discussed, even though its validity has been questioned since its introduction in 1820s. Here we first show that LLM is a crude approximation to the law of mass action, the state of art theory of biochemical reactions, and the LLM model is less accurate than two other approximations to the law of mass action—the Synthesizing Unit model and the Additive model. We corroborate this conclusion using empirical datasets of algae and plants grown under two co-limiting substrates. Based on our analysis, we show that when growth is modeled directly as a function of substrate uptake, the LLM model improperly restricts the organism to be of fixed elemental stoichiometry, making it incapable of consistently resolving biological adaptation, ecological evolution, and community assembly. When growth is modeled as a function of the cellular nutrient quota, the LLM model may obtain good results at the risk of incorrect model parameters as compared to those inferred from the more accurate Synthesizing Unit model. However, biogeochemical models that implement these three formulations are needed to evaluate which formulation is acceptably accurate and their impacts on predicted long-term ecosystem dynamics. In particular, studies are needed that explore the extent to which parameter calibration can rescue model performance when the mechanistic representation of a biogeochemical process is known to be deficient.