Serum-derived biomarkers had a limited role in diagnostic and therapeutic decision making of multiple sclerosis (MS), Alzheimer's disease (AD) and other neurodegenerative diseases until recently. A number of biomarkers (matrix metalloproteinase-9 (MMP-9), chemokine ligand 13 (CXCL-13), Chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL)) have been validated in CSF to correlate with disease acuity, drug response or prediction of long-term course of disease. However, because the value of biomarkers hugely depends on the possibility of longitudinal measurement, which is not possible for CSF-based measures in routine clinical practice, these biomarkers had not added to the diagnostic armamentarium in clinical practice. Objective: To highlight the current status of blood-derived NfL as drug response marker for clinical trialing and individual monitoring. The advent of higher sensitivity assay platforms like the single molecule array (SIMOA) allowed to compensate for the lower levels of CNS-derived markers in blood as compared to CSF. NfL is the first example for the transition from CSF- to serum-based measurements of candidate biomarkers. In many independent retrospective studies this highly specific marker for neuronal damage has been shown to correlate with clinical and MRI features of inflammatory and degenerating processes. NfL may become a disease progression endpoint in clinical trials for MS and AD. The current limitations for its routine use for individual patients, and the roadmap to overcome them will be discussed.