Drug and therapy screening in models of epilepsy have made considerable advances in recent years. Rodent models of seizures are widely used in drug development and have helped to evaluate several approved antiseizure drugs (ASDs) over the last four decades. However, current ASDs are only fully effective in approximately two-thirds of patients, with the remaining populations experiencing drug-refractory seizures. Advances in understanding of additional model systems have provided new avenues for screening and evaluation of novel therapies in epilepsy. Zebrafish and Drosophila systems allow for high-throughput (vs. rodent assays) screening and drug repurposing studies and can be adapted for specific genetic populations. Similarly, mouse models based on genetic mutations corresponding to human pathology can be used and manipulated to study pathophysiology and screen novel compounds. Special populations of epilepsy, such as individuals developing seizures arising from central nervous system infection, can be modeled by viral-induced epilepsy models. The application of chemically induced seizures has been streamlined into moderate throughput assays in mice subjected to intra-amygdala or intra-hippocampal kainic acid, generating mice with repetitive seizures and other behavioral characteristics consistent with temporal lobe epilepsy. Finally, patient-derived induced pluripotent stem cells offer an opportunity to study patient-derived organoids, in the context of patient-specific genetic backgrounds, where drug screening can be used as a personalized medicine approach. These new approaches to drug development offer opportunities to complement and improve upon traditional screening approaches in rodents, in an effort to improve approaches to hard-to-treat epilepsy conditions.