Infection with filarial nematodes remains endemic in several countries worldwide and some of these infections are commonly associated with severe disease. The elimination of lymphatic filariasis relies on drug administration using the three drugs currently available for treatment: diethylcarbamazine, albendazole, and ivermectin. However, development of drug resistance is a reported phenomenon. The issue of resistance to antihelminthics used in humans has become increasing importance since the global program to eliminate lymphatic filariasis is implemented in larger population groups and the duration of the program is increasing. Recently, ivermectin resistance has been reported in Ghana, and widespread of resistance to benzimidazole (such as albendazole) is present because specific mutations in the gene encoding β-tubulin have been associated with drug resistance. Moreover, it is well known that diethylcarbamazine susceptibility is not 100% for lymphatic filariasis treatment. A review of the mechanisms of resistance to these antihelminthics is necessary in order to optimize the treatment for human lymphatic filariasis.