This Pharmacological Perspective describes the pathway that, starting from the deep understanding of ankyrins — a family of proteins with high variability-binding and high specificity-binding characteristics — led to the development of a new class of recombinant-binding proteins, the DARPins (designed ankyrin repeat proteins). These are envisaged as alternatives to mAbs and related biologics, with the potential to overcome certain shortcomings of mAbs. DARPins have relatively low molecular weights (14–21 kDas) and more favorable PK profiles than mAbs, are stable proteins that can be easily produced in Escherichia coli and can be used in their monovalent form or conjugated to other moieties, for example, polyethylene glycol (PEG) to enhance their half-life. DARPins can also be engineered to produce bi-specific or tri-specific compounds that bind different epitopes of the same target or two different targets. Abicipar, a first-in-class anti-VEGF-A DARPin had similar efficacy compared to anti-VEGF biologics (bevacizumab, ranibizumab) in preclinical studies and was not inferior to ranibizumab in the treatment of age-related macular degeneration (AMD) with a reduced number of intravitreal injections. Abicipar has recently been submitted for regulatory approval for use in AMD.