The identification of clinically relevant biomarkers for neurological diseases poses unique challenges. These include an historical lack of availability of relevant tissues from the site of pathology, relatively poorly matured techniques for disease diagnosis, the complexity and cellular heterogeneity of the brain, and a clear deficiency of models for functional validation of candidate biomarkers. Here, the unique challenges that neurological disorders introduce to biomarker discovery are described and how modern technological advances in genomics, proteomics and metabolomics are overcoming these obstacles and are driving the discovery of novel biomarkers to improve early diagnosis and therapeutic treatment is discussed.