Filarial nematodes infect more than 150 million people worldwide and are responsible for diseases including elephantiasis, river blindness and tropical pulmonary eosinophilia. Antifilarial agents that can kill all the stages in the life cycle of causative filariae have yet to be developed. Very little effort has been made towards rational drug design, employing knowledge gained from studies of the biochemistry and physiology of filarial worms and of their interactions with their specific vertebrate hosts. In this review, we highlight the research and development of rational antifilarial agents and we discuss the pitfalls since the discovery of diethylcarbamazine, the only drug of choice for controlling filariasis, despite its adverse side effects.