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Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administration and site-specific, implant mediated drug delivery. Specifically, SMEPT offers the flexibility of delivering multiple drugs – individually as monotherapy, in sequence, or as a combination therapy, all of which is also accomplished in a site-specific manner. This technology is also unique for site-specific synthesis of drugs with short half-life, such as nitric oxide. This review presents historical development of SMEPT from early reports to the most recent examples, and also outlines potential avenues for subsequent development of this platform.