Translational Chemical Biology: Gap assessment for advancing drug discovery, development, and precision medicine Mukund Chorghade, Michael Liebman, Gerald Lushington, Stephen Naylor and Rathnam Chaguturu Remember the old advice that you should “dance with the one who brought you”? Translational researchers would do well to heed this adage. As yesterday’s lead molecule enters today’s clinical trial, the standard operating script seems to call for product developers and clinicians to push away the originating basic scientists, lest their lofty impractical ideals disrupt a delicate balance of strategic compromise. Indeed many scientists may not understand the competing push and pull of efficacy vs. toxicity and quality vs. production costs. They do, however, know the molecule in question intimately. Their insight into subtle vagaries of the incumbent chemical biology can prove invaluable in clearing unexpected hurdles. The sophisticated techniques they applied to advance the molecule this far have not lost their analytical magic. They may very well save your bacon! Translational research should never be considered a relay race hand-off, but rather a march together, hand-in-hand, toward a shared victory. In order to foster pragmatic collaboration, we endeavor to examine key technologies that not only enable early stage discoveries, but can also bridge the late-stage pitfalls that may threaten promising drug candidates on the path to market. Translational chemical biology sits at the nexus of chemistry and biology. While the application of chemical biology principles helps in the designing of a bona fide chemical probe, it is translational chemical biology that helps translate basic research in to meaningful clinical applications. This trajectory of chemical biology to its applied domain is interdisciplinary, and one that is yet to be mastered by academia. Successful outcome of any translational chemical biology effort is guided by several key factors: the impact of precision medicine, the reality of the “valley of death”, and what natural compounds and their clinical use can teach us. These issues are critical to improving drug development and lowering barriers to their translation into clinical utility and commercial value. Target-based drug discovery, a solely bottom up rather than top down approach, limits effective translation, particularly when viewed as the progression from laboratory to clinic. Observational therapeutics, guided by the principles of reverse pharmacology-the bedrock of traditional medicine but lately forgotten by the pharmaceutical industry, holds the key to the bench to bedside holistic seesaw pendulum.