The last half-century has provided all of the (few) drugs currently used to treat human helminthiases. Concern regarding the long-term utility of these drugs, given how readily resistance evolves in the veterinary-agricultural sector, spurs the discovery of new chemical entities. We review the approaches and technologies in use to identify anthelmintics and discuss a number of drug discovery paradigms that may prove pivotal to the next half-century of anthelmintic development.