A new study by Li et al. implicates the normally latent human endogenous retrovirus HERV-K in the pathogenesis of amyotrophic lateral sclerosis (ALS). Using RT-PCR and immunostaining, the authors detected the expression of HERV-K in post-mortem brain tissue samples from patients with sporadic ALS. Transfection of the HERV-K env gene into human neuronal cultures or activation of endogenous HERV-K using CRISPR–Cas9 decreased cell numbers, suggesting that the HERV-K Env protein may contribute to neuronal death. Transgenic mice expressing env exhibited progressive motor dysfunction, loss of motor neurons and other pathological changes characteristic of ALS. Further experiments demonstrated that the host DNA-binding protein TDP-43, which is overexpressed in ALS, binds to the HERV-K long terminal repeat and induces expression of the virus. The authors suggest that blocking the activation and replication of HERV-K may alter the course of disease in patients with ALS.