Lymphatic filariasis (LF) is a disease targeted for elimination. The global strategy is a once-yearly, single-dose, two-drug regimen utilised by communities at risk for LF, with the goal of reaching 80% population coverage yearly, for at least 5 years, in order to interrupt transmission of LF. Where onchocerciasis is co-endemic, the regimen is ivermectin 200 - 400 microg/kg plus albendazole 400mg; elsewhere, the regimen should be diethylcarbamazine 6 mg/kg plus albendazole 400mg. This paper reviews in detail the evidence for the efficacy and safety of these two-drug regimens underpinning the global strategy and makes recommendations for future developments in chemotherapy for LF, focusing on unresolved issues. These include optimal frequency, duration and end point of treatment, tools for monitoring successful therapy and means for detecting the potential development of resistance to any of the three antifilarial drugs on which the Global Programme to Eliminate LF depends.