During the early 1990ies, genome research has shifted to common diseases, driven by the intuitive but unproven hypothesis that for common disorders, common genetic risk factors must exist. Today, after almost two decades of genome-wide association studies (GWAS), there is consensus that the Common Disease-Common Variant hypothesis does not apply to the vast majority of common disorders. While the GWAS community is scaling up cohort sizes even further to include rare disease associated variants, others are replacing this approach by high-throughput sequencing (HTS) in their quest for important genetic factors in the etiology of common disorders. Given the enormous genetic heterogeneity of common disorders, however, there is no guarantee for the success of either of these strategies. Therefore, single gene disorders have re-emerged as a hot topic in genome research, also because HTS techniques have greatly facilitated their molecular elucidation. Moreover, contrary to disease associated markers, disease-causing mutations often provide direct insights into the underlying pathogenic mechanisms. Single gene disorders are mostly severe; for most of them, the fundamental defect is still unknown, and collectively, they are not at all rare. This is certainly true for early onset intellectual disability (ID) and related disorders, the most common reason for referral to genetic services and one of most costly diagnoses worldwide. Genetic and molecular studies have dissected ID into many hundred distinct genetic entities, thereby providing the basis for their diagnosis, prevention and even therapy. Further progress in this field can be expected from the introduction of whole-genome sequencing as a first-line diagnostic test, which will not only revolutionize genetic health care but will also shed more light on the function of human genes and the human genome as a whole.