Seizures are complex electrophysiological disturbances affecting one or more populations of brain neurons. Seizures following test article (TA) exposure pose significant challenges in drug development. This paper considers the diverse neurological manifestations, mechanisms, and functional and structural assessments needed to investigate TA-related seizure liabilities, with a particular focus on nonclinical species. Accurate discrimination of seizures from convulsions (irregular involuntary body and/or limb movements) and the nuanced presentation of different seizure types (partial vs. general) and phases (prodromal, ictal, and postictal) are essential for discerning their clinical implications. In nonclinical safety testing, the most direct evaluation method to confirm existence of seizures is electroencephalography (EEG) while clinical endpoints (e.g., functional observational batteries [FOB], comprehensive neurological examinations) and neuropathological findings (e.g., neuronal necrosis in tissue sections, raised biomarker levels in cerebrospinal fluid or serum) can indicate a seizure liability and provide additional guidance to identify the origin, frequency, and severity of seizures needed to align nonclinical effects with clinical relevance. In general, the regulatory perspective is that seizures identified in nonclinical species as well as potential risk management strategies (e.g., safety margin considerations, dosing paradigms, and clinical monitoring) translate effectively for purposes of clinical risk assessment.