Methylphenidate (MPH) is one of the most commonly prescribed medications to treat attention deficit hyperactivity disorder (ADHD). Despite the elevated rates of ADHD in children with epilepsy, few studies have examined the use of MPH in this population. Case reports have warned about new-onset seizures in patients treated with MPH, and drug-drug interactions between MPH and antiepileptic drugs (AEDs), as well as antidepressants. However, retrospective chart reviews, open-label trials and controlled trials of MPH in patients with epilepsy and ADHD have noted significant improvements in ADHD symptoms without an exacerbation of seizures or an adverse effect on AED serum levels. This paper reviews the chemistry and mechanisms of action of MPH, as well as preclinical, premarketing clinical trials and postmarketing data relevant to its use in patients with ADHD and epilepsy.