This article reviews the current position of phenobarbital using articles published since 2000 and speculates on its likely future contribution to epilepsy care. Over the last decade there have been no major double-blind randomized placebo-controlled or comparative trials with phenobarbital. Previous studies have suggested that phenobarbital is as effective in monotherapy as phenytoin and carbamazepine. Several observational studies undertaken in developing countries over the last decade have confirmed its efficacy and safety for the common epilepsies. This was particularly so in the substantial demonstration project undertaken in rural China under the auspices of the World Health Organization in partnership with the International League Against Epilepsy and International Bureau for Epilepsy. Phenobarbital is still widely used for neonatal and childhood seizures and for drug-resistant convulsive and nonconvulsive status epilepticus. Recent data have confirmed in a prospective cohort of women taking phenobarbital as monotherapy that the drug can be associated with a range of congenital defects in exposed infants. Much effort has gone into exploring the apparent contradiction of higher withdrawal rates due to cognitive and behavioral side effects in studies undertaken in developed countries but not in those sited in the developing world. A raft of data over the last 10 years, including a systematic review, showed no important differences between the tolerability of phenobarbital compared to that with other antiepileptic drugs. Finally, cognitive test scores and mood ratings in 136 people with epilepsy receiving phenobarbital for a year were similar to those in 137 age-, sex-, and education-matched controls in a number of Chinese villages. Indeed, there were some cognitive gains in the patients possibly due to improved seizure control. Phenobarbital is still the most cost-effective pharmacologic treatment for epilepsy. All these data predict a healthy future for phenobarbital, particularly in helping to close the treatment gap in low- and middle-income countries during its second century of clinical use.