An overview of the theoretical/computational methods that allow the study of the thermodynamic stability of the polymer blends for photovoltaics is provided. After discussing the fundamental concepts of thermodynamic blend stability and solubility, including mixing enthalpy and the Flory–Huggins theory, some experimental approaches to determine the interaction parameter and the stability in organic photovoltaic (OPV) are briefly discussed, and the advances in the modeling of polymer blends based on the use of atomistic simulations and multiscale modeling are reviewed. An outlook on the modeling strategies that can have a strong impact on the design of stable blends and to the commercial OPV technologies is given. In particular, the main directions along which major developments are expected are envisaged: multiscale models with improved accuracy or machine learning methods applied to large ab initio datasets, as well as a judicious combination of the two strategies.