More than 2 billion people are infected with helminth parasites across the globe. The burgeoning drug resistance against current anthelmintics in parasitic worms of humans and livestock requires urgent attention to tackle these recalcitrant worms. This review focuses on the advancements made in the area of helminth drug target discovery especially from the last few couple of decades. It highlights various approaches made in this field and enlists the potential drug targets currently being pursued to target economically important helminth species both from human as well as livestock to combat disease pathology of schistosomiasis, onchocerciasis, lymphatic filariasis, and other important macroparasitic diseases. Research in the helminths study is trending to identify potential and druggable targets through genomic, proteomic, biochemical, biophysical, in vitro experiments, and in vivo experiments in animal models. The availability of major helminths genome sequences and the subsequent availability of genome-scale functional datasets through in silico search and prioritization are expected to guide the experimental work necessary for target-based drug discovery. Organized and documented list of drug targets from various helminths of economic importance have been systematically covered in this review for further exploring their use and applications, which can give physicians and veterinarians effective drugs in hand to enable them control worm infections.