Next-generation sequencing (NGS) technologies are now routinely used for gene identification in Mendelian disorders. Setting up cost-efficient NGS projects and managing the large amount of variants remains, however, a challenging job. Here we provide insights in the decision-making processes before and after the use of NGS in gene identification studies. Genetic factors are thought to have a role in ~70% of all epilepsies, and a variety of inheritance patterns have been described for seizure-associated gene defects. We therefore chose epilepsy as disease model and selected 35 NGS studies that focused on patients with a Mendelian epilepsy disorder. The strategies used for gene identification and their respective outcomes were reviewed. High-throughput NGS strategies have led to the identification of several new epilepsy-causing genes, enlarging our knowledge on both known and novel pathomechanisms. NGS findings have furthermore extended the awareness of phenotypical and genetic heterogeneity. By discussing recent studies we illustrate: (I) the power of NGS for gene identification in Mendelian disorders, (II) the accelerating pace in which this field evolves, and (III) the considerations that have to be made when performing NGS studies. Nonetheless, the enormous rise in gene discovery over the last decade, many patients and families included in gene identification studies still remain without a molecular diagnosis; hence, further genetic research is warranted. On the basis of successful NGS studies in epilepsy, we discuss general approaches to guide human geneticists and clinicians in setting up cost-efficient gene identification NGS studies.European Journal of Human Genetics advance online publication, 25 November 2015; doi:10.1038/ejhg.2015.251.