Recombinant DNA technologies revolutionized medicine. Herein, the approvals and mechanistic basis of biologics-based medicines are analyzed. The overall and relative rate of FDA approvals for recombinant proteins grew from the 1980s through the first half-decade of the new millennium. Over time, the number of biologics gaining approval for an orphan indication has climbed to more than 50% in the current decade. The field has been dynamic in terms of the types of biologics, indications targeted and the mechanistic basis of drug activity. Despite impressive increases in recombinant-protein-based medicine, the rate of new biologics approvals could have leveled out.