Neglected helminthic diseases cause many social, economic and health care challenges in developing countries. The high number of patients suffering from these parasitic infections and the lack of sufficient treatment options represent severe problems. Research on new drugs and therapies to meet this urgent requirement has to be intensified. This review focuses on infections caused by four helminthic parasites, which have been declared as neglected diseases by the World Health Organization: namely drancunculiasis, lymphatic filariasis, onchoceriasis, and schistosomiasis. They show a considerable overlap in their world-wide prevalence and treatment strategies. Nevertheless, treatment is not without complications. The most efficient lymphatic filariasis drug, diethylcarbamazine, causes severe adverse effects in onchocerciasis patients and completely fails in the treatment of drancunculiasis. In this review, we discuss these incongruities at the molecular and cellular level. Furthermore, established or investigational drug combination regimens are highlighted. In the past years, progress has been made in the area of schistosomiasis and onchocerciasis. The molecular biology of underlying mechanisms, signalling pathways and related targets affected by drug therapy are discussed in detail. Finally, successful treatment strategies and remaining future challenges are summarized.