The rapid evolution of anthelmintic resistance in a number of parasites of livestock and domesticated animals has occurred in response to widespread use of anthelmintics for parasite control, and threatens the success of parasite control of species that infect humans. The genetic basis of resistance to most anthelmintics remains poorly resolved. Genome-wide approaches are now accessible due to recent advances in high-throughput sequencing, and are increasingly applied to characterize traits including drug resistance. Here, we discuss why traditional candidate gene studies have largely failed to define the genetics of resistance, and why - and in what circumstances - we expect genome-wide approaches to shed new light on the modes of action and the evolution of resistance to anthelmintic compounds.