Obesity is a polygenic chronic condition, and dysregulation in multiple underlying energy balance processes drives the obese phenotype. Lifestyle changes can be difficult to sustain long term, and anti-obesity drugs can be an advantageous component of a successful weight loss plan. However, due to lack of efficacy or adverse safety profiles, there is currently a limited selection of anti-obesity drugs on the market. This, coupled with the notable interindividual variability in efficacy of approved treatments, represents a significant unmet medical need. In this review, we will highlight this variability in weight loss response to these existing anti-obesity compounds and discuss how underpinning genetic variation is associated with weight loss outcomes. Existing research in the field of pharmacogenomics and obesity drugs will be highlighted, as will possibilities for future focus. We will conclude by exploring examples of successful pharmacogenomics studies, and also by asking how pharmacogenomics can be built into the drug development pipeline for the benefit of patients and pharmaceutical companies alike.