Due to their excellent catalytic efficiency, stereoselectivity and sustainability as well as the complementary retrosynthetic logic of biotransformations, the pharmaceutical industry recently started to embrace the power of new biocatalysis tools in the production of active pharmaceutical intermediates (APIs). As a testament to this, the Merck process chemistry team recently developed fully biocatalytic syntheses of anti-HIV and immunooncology drugs islatravir (MK-8591) and MK-1454, respectively. By merging highly selective biotransformations with versatile chemical synthesis, chemoenzymatic synthesis offers further improved synthetic versatility and efficiency in the manufacturing of APIs. Over the past decade, through mechanism-guided enzyme repurposing and evolution, new-to-nature biocatalytic reactions which were unknown in nature's vast catalytic repertoire have emerged as powerful tools for synthetic applications. Despite the promise of new-to-nature biocatalysis, the evolution and integration of these newly developed toolkits into the chemoenzymatic synthesis of clinically important therapeutics remains largely underdeveloped.