Protein scaffolds represent a new generation of universal binding frameworks for use as future immunopharmaceuticals to complement the expanding repertoire of therapeutic monoclonal antibodies. Here, we review recent literature describing advances in protein scaffold development, including efforts to engineer the minimal immunoglobulin-based binding-domain and molecular library design. Several diverse protein folds are currently under development on the basis of modular construction, a strategy also observed in families of naturally evolved immune receptors. We describe potential therapeutic and intracellular applications where scaffold-specific features provide distinct advantages for targeting of non-conventional antigens and comment on the scientific progress and validation of several designed scaffolds in the voyage towards first-in-human trials.