For the reasons discussed here, we think whole-genome- or exome-based approaches are currently most suited for diagnostic implementation in genetically heterogeneous diseases, initially to complement and later to replace Sanger sequencing, qPCR and genomic microarrays. Patients do need to be counseled for the possibility of receiving medically relevant information not related to the disease under investigation, but this chance can be minimized by a focused data-analysis process. Establishing the pathogenicity of individual genetic variants remains a daunting task, requiring novel bioinformatic tools and high-throughput functional approaches, but at least we can now be more sure that we have not missed relevant genetic variation.