Epilepsy is one of the most common neurologic disorders, affecting about 50 million people around the world. It is recognized that around 50% of patients with newly diagnosed epilepsy become seizure-free with the first drug treatment, so the choice of first antiepileptic drug is crucial. This paper provides a comprehensive overview of zonisamide as monotherapy for partial seizures, with special attention to the possibility of a once-daily regimen. The available data suggest that zonisamide is an effective and well tolerated option as monotherapy. Once-daily dosing is indicated, considering the long plasma half-life and linear pharmacokinetics of the drug. Zonisamide 300 mg was shown to be noninferior to carbamazepine 600 mg in terms of efficacy and safety, but even lower doses may be effective. Finally, the broad spectrum of efficacy in different seizure types, the low drug interaction potential, and the possibility of weight loss make zonisamide a preferred option in many epilepsy practices. Further data on monotherapy, especially in special populations, such as women of childbearing potential, are needed.