Prospective population based-registers of amyotrophic lateral sclerosis (ALS) have operated in Europe for over two decades, and have provided important insights into our understanding of ALS. Here, we review the benefits that population registers have brought to the understanding of the incidence, prevalence, phenotype and genetics of ALS and outline the core operating principles that underlie these registers and facilitate international collaboration. Going forward, we offer lessons learned from our collective experience of operating population-based ALS registers in Europe for over two decades, focusing on register design, maintenance, identification and management of bias and the value of cross-national harmonisation and integration.