Small protein domains that bind to protein– protein contact sites are important tools for drug discovery and biotechnology. But attempts to find bona fide "protein mimics" are often thwarted by the difficulty of making contacts between small linear molecules and flat protein surfaces. Reineke et al. tackle this problem using a synthetic, combinatorial approach to generate a discontinuous binding site on interleukin-10 that can bind tightly to its ligand, an IL-10 monoclonal antibody (p. 271).