While the therapeutic biologics are dominated by therapeutic proteins, particularly monoclonal antibodies, a wide range of non-protein therapeutic biologics are rapidly gaining ground both in clinical studies and approved products. Many of these first-in-class therapies provide novel treatment modalities and address previously untreatable conditions or undruggable targets. In particular, novel treatments for rare genetic disorders and qualitatively different oncology therapeutics have been approved in the last two years. This review discusses recent advances in peptide, nucleic acid, carbohydrate, vaccine, and cell-based therapies as well as the manufacturing and commercialization challenges associated with these novel therapeutics.