Metabolic modeling is a necessary part of the analysis of isotopic labeling data that is being obtained in the brain and other organs. Here are explained the basic principles of metabolic modeling of isotopic labeling studies, particularly with regard to ¹³C isotopic measurements performed in vivo. The basic elements needed to simulate isotopic flows are described, and how to combine them to perform modeling analyses is explained. Procedures to introduce and evaluate model constraints and simplifications are discussed. The basic principle of isotopomer analysis is explained, as are mechanics of least-squares fitting of simulations to data. Closely related to the fitting is the effect of data scatter, which is discussed in the context of the non-normal distributions of uncertainty that are often seen with ¹³C labeling measurements in vivo. This article is meant to provide a general background for investigators to begin to apply metabolic modeling analysis to ¹³C isotopic labeling studies performed in vivo.