The most important challenge of ALS remains finding biomarkers. Clinical features remain of key importance in the diagnosis and for follow up. Neurophysiology remains difficult to use in clinical trials. Neuroimaging have some utility for upper motor neuron integrity and function. Among proteins and chemical markers, one of the most promising marker is the level of Nogo in muscle biopsy. In CSF, many candidate proteins have been suggested but their sensitivity and specificity remains disappointing. Recently, -omics technologies have been applied to try to discover biomarkers in ALS, including genomic, proteomic and metabolomic methodologies.