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Monoclonal antibodies can bind with high affinity and high selectivity to their targets. As a tool in therapeutics or diagnostics, however, their large size (∼150 kDa) reduces penetration into tissue and prevents passive cellular uptake. To overcome these and other problems, minimized protein scaffolds have been chosen or engineered, with care taken to not compromise binding affinity or specificity. An alternate approach is to begin with a minimal non-antibody scaffold and select functional ligands from a de novo library. We will discuss the structure, production, applications, strengths, and weaknesses of several classes of antibody-derived ligands, that is, antibodies, intrabodies, and nanobodies, and nonantibody-derived ligands, that is, monobodies, affibodies, and macrocyclic peptides. In particular, this review is focussed on macrocyclic peptides produced by the Random non-standard Peptides Integrated Discovery (RaPID) system that are small in size (typically ∼2 kDa), but are able to perform tasks typically handled by larger proteinaceous ligands.