Due to the new developments in science and computing technology, today more than ever new promising approaches for the therapy of rare diseases are emerging such as ERT, Ab immunotherapy, proteins, gene therapy, stem cells, regenerative medicine, RNA-based therapies and small molecules. As a result, the diagnostic of rare disease patients becomes of the outmost importance. Due to the nature of the rare diseases, their insufficient description and known natural history as well as due to the lack of general knowledge of the practitioners and none in the least the necessity of rapid diagnostic, the burden of correct identification of the affected patients resides mostly on screening national programs and private targeted screening projects. Most of the typical screening projects will be 1-tier testing which is insufficient to correctly diagnose a rare disease patient. A more holistic approach is necessary including classical enzymatic testing, biomarkers (molecular fingerprint) quantification and confirmation by genetics. Large scale multiple tier screening include automatic sample preparation, multiple reaction monitoring mass spectrometry (MRM-MS), next generation sequencing and even CNV determinations. This approach is targeted for specific rare disease (e.g. Niemann-Pick, Gaucher) and all analyses are performed out of a minimal amount of sample. However, with the new field of untargeted metabolic profiling, combined with untargeted gene sequencing techniques such as genomic panels – the screening possibilities will be unprecedented, capable to compensate to the understanding of the disease and for the overlapping clinical pictures of specific diseases.