Drug-induced weight alteration can be a serious side effect that applies to several therapeutic agents and must be referred to in the respective approved labeling texts. The side effect may become health threatening in case of significant weight change in either direction. Several antiepileptic drugs (AEDs) are associated with weight gain such as gabapentin, pregabalin, valproic acid, and vigabatrin and to some extent carbamazepine. Others are weight neutral such as lamotrigine, levetiracetam, and phenytoin or associated with slight weight loss as, e.g., felbamate. The focus of this chapter is on the two AEDs causing strong weight loss: topiramate and zonisamide. For both drugs, several molecular mechanisms of actions are published. We provide a review of these potential mechanisms, some of which are based on in vivo studies in animal models for obesity, and of clinical studies exploring these two drugs as single entities or in combinations with other agents.