Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now recognized as a disease spectrum with overlapping genetic, molecular, and pathological features, including TDP-43 dysfunction, RNA processing abnormalities, and neuroinflammation. Biomarker advancements, such as T cell subtypes in ALS and HDGFL2 in both diseases, are improving diagnosis and treatment monitoring, while personalized therapies like antisense oligonucleotides (ASOs) and CRISPR-based approaches show promise in modifying disease progression. Neuroinflammation, driven by microglial activation and cytokine dysregulation, presents key therapeutic targets for immune-modulating and anti-inflammatory interventions. Current ALS treatments provide limited benefits, and no FDA-approved therapies exist for FTD, highlighting the need for novel approaches. Stem cell-based therapies offer potential neuroprotection and immune regulation, with allogeneic transplants holding more promise than autologous ones, despite immune rejection challenges. Advances in gene editing and immune-evasive strategies could enhance transplantation outcomes, paving the way for personalized, off-the-shelf treatments for ALS and FTD.