The ever-quickening pace of breathtaking advances in our understanding of disease biology has implicitly promised a profusion of drugs that will dramatically improve human health and well-being. Realization of this promise remains frustratingly elusive. Where are all the new drugs? We contend that a major contributing factor is the limitations in target scope of the two well-establish drug modalities, namely small molecules and protein therapeutics. Addressing this targetability gap will require the discovery and development of entirely new structural classes of drugs and the pioneering of new strategies for finding them. Any fundamentally new class of drug introduces discovery challenges that fall outside the hard-won risk-mitigation paradigms for established classes of drugs, hence the reluctance of pharma, biotech and even the investment community to fully embrace next-generation therapeutic modalties. Learning how to navigate these challenges will therefore fall disproportionately to the academic community, and will not be easy or happen quickly. That said, recent developments in the field of next-generation therapeutics give reason to be cautiously optimistic.