The need for improved antiepileptics is clearly mandated despite the existence of multiple existing medicines from different chemical and mechanistic classes. Standard of care agents do not fully control epilepsies and have a variety of side-effect and safety issues. Patients typically take multiple antiepileptic drugs and yet many continue to have seizures. Antiepileptic-unresponsive seizures are life-disrupting and life-threatening. One approach to seizure control is surgical resection of affected brain tissue and associated neural circuits. Although non-human brain studies can provide insight into novel antiepileptic mechanisms, human epileptic brain is the bottom-line biological substrate. Human epileptic brain can provide definitive information on the presence or absence of the putative protein targets of interest in the patient population, the potential changes in these proteins in the epileptic state, and the engagement of novel molecules and their functional impact in target tissue. In this review, we discuss data on two novel potential antiepileptic drugs. CERC-611 (LY3130481) is an AMPA receptor antagonist that selectively blocks AMPA receptors associated with the auxiliary protein TARP γ-8 and is in clinical development. KRM-II-81 is a positive allosteric modulator of GABA receptors selectively associated with protein subunits α2 and α 3. Preclinical data on these compounds argue that patient-based biological data increase the probability that a newly discovered molecule will translate its antiepileptic potential to patients.