Significance Fibroblast activation protein (FAP) has recently emerged as a tumor-associated antigen with abundant and selective expression in the majority of human solid malignancies. To the best of our knowledge, OncoFAP is the highest-affinity small organic FAP ligand reported to date, with a dissociation constant of 680 pM, as measured by fluorescence polarization. Upon intravenous administration, both fluorescent and radiolabeled OncoFAP derivatives exhibited a rapid and selective accumulation in FAP-positive tumors, sparing normal tissues. OncoFAP was also used as a modular component for the generation of therapeutic products, enabling the targeted delivery of a potent beta-emitter (lutetium-177), of fluorescein-specific chimeric antigen receptor (CAR) T cells or of highly cytotoxic auristatin derivatives to FAP-positive tumors in vitro and in vivo.