The past, present, and future of enzyme-based therapies

•An overview of applications of enzyme based therapies (EBTs).•Provides historical, clinical, and regulatory context for EBT market growth and decline.•A review of both approved and investigational therapies.•Discusses challenges facing EBTs that could be addressed with enzyme engineering.•Specific, relevant examples of targets for enzyme engineering for improved EBTs. Enzyme-based therapeutics (EBTs) have the potential to tap into an almost unmeasurable amount of enzyme biodiversity and treat myriad conditions. Although EBTs were some of the first biologics used clinically, the rate of development of newer EBTs has lagged behind that of other biologics. Here, we review the history of EBTs, and discuss the state of each class of EBT, their potential clinical advantages, and the unique challenges to their development. Additionally, we discuss key remaining technical barriers that, if addressed, could increase the diversity and rate of the development of EBTs.