We advanced the concept of biosynthonics five years ago as a solution for resuscitating the productivity of small-molecule drug pipelines across the pharmaceutical industry. Biosynthonics employs metagenomics and metabolic engineering to mine pharmacoactive structures that are otherwise beyond the reach of synthesis platforms that are currently utilized for drug discovery and lead optimization. Biosynthonics can be harnessed to generate unprecedented quantities of truly novel pharmacoactive structures, which, in turn, can have a game changing effect on the productivity and success rate of drug discovery and early clinical testing in the pharmaceutical industry. However, the impact of biosynthonics on the productivity and cost of product development is somewhat constrained owing to pervading inefficiencies in other parts of the drug discovery and development workflow. Herein, we update our vision for improving the productivity and diminishing the cost of drug discovery and development. Although biosynthonics remains a key piece in our strategy, we discuss how its integration with emerging paradigms in chemical engineering such as information science and materials science, as well as innovations in pharmaceutical manufacturing will drive the next generation of projects in the pharmaceutical industry. In many regards, our updated vision is more pragmatic and leverages the competencies of the pharmaceutical industry more effectively. We have already implemented this vision in our laboratory and early results have been very encouraging. Some of these examples have been detailed in the current work.