More than 5000 genetic disorders have a known molecular basis, and approximately 40% involve the nervous system. Until the advent of next-generation sequencing (NGS), most patients did not receive a molecular diagnosis, even if they had disorders with undisputed genetic etiology. However, the immense value that NGS offers in identifying novel disease genes remains underexploited fully due to the increased complexity in interpreting genetic sequences. In this chapter, we describe the advantages, indications, and limitations of NGS platforms in the process of providing a clinical diagnosis for inherited atypical parkinsonian disorders. We follow this with discussion of the strategies involved in variant filtration, clinical interpretation, and validation for novel variants. We also evaluate the de novo variant phenomenon and focus on the underlying reasons of a rather low clinical molecular diagnosis rate, even with NGS. Although a genetic diagnosis can end the diagnostic odyssey and need for ongoing investigation, a change in diagnosis may bring about different psychological, social, and economic consequences for individuals and their families. Many centers have developed multidisciplinary teams who meet on a regular basis to discuss these issues, whenever possible. Disease-specific or phenotype-specific specialists should be involved, and the consensus for all genomic tests is to provide pretest and posttest genetic counseling. Finally, we discuss the available bioinformatics approaches and databases that are helping clinicians with big data management, analysis, and phenotype–genotype correlation.