Using high throughput next-generation sequencing to simultaneously search large number of genes for pathogenic mutations has numerous advantages. It decreases the pressure to narrow the differential diagnosis for diseases with overlapping phenotypes, can identify entirely new causative private mutations when no good candidate genes are available, and shorten the patients diagnostic odyssey. The Laboratory of Personalized Genomic Medicine at Columbia University started offering mitochondrial genome, partial and whole exome sequencing for clinical diagnostic purposes in January 2013. In my talk I will highlight the effectiveness of next-gen sequencing in diagnosing neurological and neurodegenerative conditions. Furthermore I will discuss the use of next-gen sequencing technologies to evaluate transcriptional and translational changes that might define these conditions in cell culture and animal model systems. Finally, I will propose some practical steps that would improve the effectiveness of next-gen sequencing diagnosis of neurodegenerative disorders and present my view of the near future based on the technologies that are available or will soon become available.