Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a distinct human epileptic syndrome. In some families, it is associated with mutations of the α4 or the β2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR). It has been suggested that these mutations are the causative factors responsible for the induction and expression of this syndrome. However, the pathogenic mechanisms leading to ADNFLE are unknown and, in this review, we discuss the following yet unresolved questions concerning the involvement of mutated nAChRs in the phenotypic development of the disorder: (1) why do seizures associated with ADNFLE arise explicitly from the frontal lobe of the neocortex? (2) why do the seizures arise mainly from sleep? (3) why does ADNFLE starts predominantly during childhood? A survey of our current knowledge on neocortical and thalamic cholinergic systems, including their ontogenetic development, leads us to the conclusion that there are, at least at the moment, no convincing answers to these questions. Furthermore, we believe that, even in those cases where mutations of the α4 or the β2 subunit of the nAChR cosegregate with ADNFLE, there must be some crucial additional factors contributing to the development of the specific symptoms of ADNFLE.