Diffusion of impurity atoms or point defect species occurs simultaneously with segregation in materials that are inhomogeneous or consisting of heterostructures. Based on thermodynamic principles, a general diffusion-segregation equation (DSE) simultaneously describing the species’ diffusion and segregation behavior has been derived. The DSE treats the diffusion-segregation problems on the same fundamental level as the diffusion problems are treated by Fick’s Laws. A critical comparison of modeling diffusion-segregation phenomena using the DSE vs. previous formulations is given. The wide range of applications of the DSE is demonstrated by several examples.