I have been fascinated by the possibilities of genomics technologies to explain the causes of human disease ever since these technologies became available. For this purpose I have built a multidisciplinary research group with expertise in genome technology, molecular biology, computational science and clinical genetics. In the beginning of this millennium I pioneered microarray-based detection of submicroscopic chromosomal copy number variations in clinical genetics. My group was the first to identify a disease gene with this approach and the first to implement microarrays for diagnostic genome profiling in mental retardation. In the last 10 years I have been using mental retardation as a model disease to learn the basic concept of genotype-phenotype correlations. To study the impact of all forms of genomic variation on human disease I recently established next generation sequencing (NGS) technology. I have obtained several prestigious scientific grants; ZonMW VIDI, ZonMW equipment grant for NGS equipment, FP6 funded AnEUploidy, FP7 funded TECHGENE and GENCODYS. I am actively involved in the coordination of Medical Genome Sequencing efforts in Europe, recently funded through an FP7 coordinated action on standards in large-scale data gathering called GEUVADIS. The combination of fundamental research, technology development and clinical application in human genetics is to me both challenging and promising. My ultimate goal is to advance medical sciences by integrating our knowledge on the impact of genome variation in routine clinical decision making.