Protein-protein interactions represent a new class of exciting but challenging drug targets, because their large, flat binding sites lack well-defined pockets for small molecules to bind. We report here a methodology for chemical synthesis and screening of large combinatorial libraries of bicyclic peptides displayed on rigid small-molecule scaffolds. With planar trimesic acid as the scaffold, the resulting bicyclic peptides are effective for binding to protein surfaces such as the interfaces of protein-protein interactions. Screening of a bicyclic peptide library against tumor necrosis factor-alpha (TNF alpha) identified a potent antagonist that inhibits the TNF alpha-TNF alpha receptor interaction and protects cells from TNF alpha-induced cell death. Bicyclic peptides of this type may provide a general solution for inhibition of protein-protein interactions.