The past few years have seen great conceptual and methodological advances in our understanding of disease mechanisms behind amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) disease spectrum. The aim for this 'Amyotrophic Lateral Sclerosis: Challenges and New Advances' review series is to promote in-depth discussions on exciting new developments in the field that may best facilitate our endeavors to fight the disease. The first article in this series, “Advances in sequencing technologies for amyotrophic lateral sclerosis research”, describes how novel long-read sequencing platforms are being used to uncover the contribution of repeat expansions and other types of structural variation. These emerging technologies may help explain missing heritability in ALS and aid our understanding of this challenging disease. Future contributions in this series will address the role of nuclear-import receptors in regulating pathological phase transitions in ALS, the need for better mouse models of ALS, the contribution of altered axonal functions of TDP-43 to early NMJ disruption in ALS, the role of TDP-43 dependent cryptic exon inclusion in ALS pathobiology, and emerging biomarkers to facilitate ALS recruitment and therapy development. As the field advances, we envision that other relevant topics would be included in this series.