This chapter presents a mechanistic approach to in silico prediction of blood–brain barrier penetration by drugs and drug-like molecules. Focus is brought to critical analysis of experimental data used for modeling; several factors affecting data quality are discussed. The main experimental techniques used for measuring brain uptake are also briefly reviewed. The chapter provides a theoretical background for obtaining physicochemically reasonable and easily interpretable predictions of passive diffusion across blood–brain barrier, as well as some general advices regarding descriptor selection and model development.