AbstractFolate‐mediated one‐carbon metabolism (FOCM) is associated with risk for numerous pathological states including birth defects, cancers, and chronic diseases. Although the enzymes that constitute the biological pathways have been well described and their interdependency through the shared use of folate cofactors appreciated, the biological mechanisms underlying disease etiologies remain elusive. The FOCM network is highly sensitive to nutritional status of several B‐vitamins and numerous penetrant gene variants that alter network outputs, but current computational approaches do not fully capture the dynamics and stochastic noise of the system. Combining the stochastic approach with a rule‐based representation will help model the intrinsic noise displayed by FOCM, address the limited flexibility of standard simulation methods for coarse‐graining the FOCM‐associated biochemical processes, and manage the combinatorial complexity emerging from reactions within FOCM that would otherwise be intractable. WIREs Syst Biol Med 2013, 5:343–365. doi: 10.1002/wsbm.1209This article is categorized under: Analytical and Computational Methods > Dynamical Methods Biological Mechanisms > Metabolism Physiology > Mammalian Physiology in Health and Disease