The management of obesity remains a major challenge. Dietary therapy often fails, whereas bariatric surgery, although successful, is demanding and applicable to a limited number of patients. Drug therapy has had many setbacks over the past 20 years because of serious adverse effects; however, several new drugs for the treatment of obesity are either licensed in some parts of the world, submitted for registration, or completing phase III trials. These include combinations (at low dose) of existing drugs, e.g., bupropion/naltrexone (Contrave), phentermine/topiramate (Qsymia), higher doses of existing drugs licensed for other indications (liraglutide, 3 mg), and new entities (lorcaserin). Substantial barriers remain, even if drugs are approved, in successfully integrating these agents into weight management practice, largely related to cost, patient acceptability, and clinician willingness to be engaged in obesity treatment. There is a need to maximize outcomes from pharmacotherapy to overcome these barriers. Strategies include patient selection (i.e. matching the drug to the individual), but neither patient phenotype nor pharmacogenomics are established to achieve this aim. Combining pharmacotherapy with optimal lifestyle interventions has been shown to increase efficacy, and ensuring that non-responding patients are withdrawn from treatment will increase overall effectiveness and minimize non-beneficial exposure of patients. This concept is already enshrined in the licensing of several new drugs. Lastly learning how to combine drugs from different classes may hold promise for the future, but historical experience with inappropriate combinations (phentermine and fenfluramine) dictates caution.