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Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to our detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, nusinersin, based on modulating the splicing behaviour of the SMN2 gene, is the first treatment which significantly alters the natural history of motor neuron degeneration. This will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, and has implications for the molecular therapy of other neurological diseases.