Ensuring effective drug concentration specifically at sites of need, while limiting systemic side effects, remains a challenge in the discovery and use of new drug molecules. Carriers targeted through biological affinity (e.g., antibodies) afford a common means of drug localization, yet often deliver considerably less than 1% of an administered drug to a desired site in the body. We report on an alternative targeting paradigm using pendant guest motifs to direct molecules to sites distinguished by a hydrogel bearing a high density of a complementary cucurbituril supramolecular host. Host-guest affinity (K eq) of 1012 M-1 serves to spatially localize ∼4% of a model small molecule within hours of its administration in mice. These high-affinity interactions furthermore ensure long-lasting retention of the model compound at the site of interest, and the site can be serially targeted upon repeated dosing. This supramolecular homing axis extends the localization of small molecule payloads beyond injectable hydrogels, enabling targeting of modified biomaterials. This approach also has promising therapeutic utility, improving efficacy of a guest-modified chemotherapeutic agent in a tumor model.