Polyketide synthases (PKSs) are large, multi-active site enzymes that synthesise a variety of bioactive molecules, notably used as antibiotics, by the repeated condensation of small acyl building blocks. The mosaic, assembly line structure of PKSs has generated interest in engineering them to produce novel bioactive molecules. A major source of the chemical diversity in polyketides is the range of building blocks used in their biosynthesis. There exist standalone enzymes that select building blocks for PKS assembly lines, called trans-acyltransferase domains. These enzymes have the potential to be used as tools to change building block use in PKSs, changing their products to produce novel polyketides. However, known trans-acyltransferase domains select for an extremely limited range of building blocks. OzmC is a proposed trans-acyltransferase from the biosynthesis of the antibiotic and cytotoxic compound, oxazolomycin. Within this biosynthetic pathway, OzmC was proposed to select for a building block that is unique among known trans-acyltransferase domains. Studies by in vitro assays analysed by intact protein mass spectrometry revealed OzmC to accept multiple different acyl building blocks. To better understand this unusual acyltransferase, the structure of OzmC was solved by X-ray crystallography which revealed that the tertiary structure of OzmC is unique among known trans-acyltransferase domains. The promiscuity of OzmC, along with its unprecedented structure among trans-acyltransferases, makes it both an interesting case within the landscape of polyketide biosynthesis and an attractive engineering target for the production of novel bioactive molecules.