Five to ten percent of all children suffer from attention-deficit/hyperactivity disorder (ADHD), which is often treated with the central nervous stimulant methylphenidate (MPH). In 2005 controversy arose due to a report of enhanced cytogenetic effects in 12 children after 3 months of MPH treatment. Since then, several prospective studies have been performed and published, which are summarized here. A table comparing the micronucleus frequencies, a marker investigated in all of these studies, is presented. An induction of cytogenetic effects by MPH was only reported in one, the 2005 study by El-Zein et al., while all other studies, with now altogether 110 MPH-exposed individuals, showed no elevation. To address the question of long-term use of MPH, we published the data of 30 chronically treated children and also saw no difference compared to untreated children. Here, we report as new follow-up data that an additional 12 months time point in a small group of 12 children who had begun MPH therapy within our published study also did not reveal elevated cytogenetic damage. Furthermore, a previously unpublished analysis of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG; a non-invasive biomarker for DNA-base oxidation and its repair) in 11 children before and after 3 months of MPH exposure yielded no significant difference. Since gene mutations may not necessarily manifest as chromosomal aberrations, micronuclei or SCEs, we discuss the available data from animal models, which also do not reveal a mutagenic potential of MPH. Although the only two available epidemiological studies do not report elevated risk for MPH exposure, the results are not conclusive yet, and further monitoring of exposed populations is suggested.