||The permeability of hydrogels for the selective transport of molecular penetrants (drugs, toxins, reactants, etc.) is a central property in the design of soft functional materials, for instance in biomedical, pharmaceutical, and nanocatalysis applications. However, the permeation of dense and hydrated polymer membranes is a complex multifaceted molecular-level phenomenon, and our understanding of the underlying physicochemical principles is still very limited. Here, we uncover the molecular principles of permeability and selectivity in hydrogel permeation. We combine the solution-diffusion model for permeability with comprehensive atomistic simulations of molecules of various shapes and polarities in a responsive hydrogel in different hydration states. We find in particular that dense collapsed states are extremely selective, owing to a delicate balance between the partitioning and diffusivity of the penetrants. These properties are sensitively tuned by the penetrant size, shape, and chemistry, leading to vast cancellation effects, which nontrivially contribute to the permeability. The gained insights enable us to formulate semiempirical rules to quantify and extrapolate the permeability categorized by classes of molecules. They can be used as approximate guiding ("rule-of-thumb") principles to optimize penetrant or membrane physicochemical properties for a desired permeability and membrane functionality.