The article reviews the emerging roles of TDP-43 and FUS/TLS in RNA processing and neurodegeneration. TDP-43 and FUS/TLS are RNA/DNA-binding proteins that have been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The identification of mutations in these proteins has shifted the understanding of ALS and FTLD pathogenesis. TDP-43 mislocalization and aggregation are common pathological hallmarks in ALS and FTLD, with 38 dominant mutations identified in TDP-43 and 30 in FUS/TLS. These mutations are associated with both familial and sporadic forms of ALS and FTLD. The article discusses the biochemical and pathological characteristics of TDP-43 and FUS/TLS proteinopathies, including their involvement in multiple steps of RNA processing, transcription regulation, splicing, microRNA processing, and cytosolic roles in RNA subcellular localization, translation, and decay. It also explores the roles of TDP-43 and FUS/TLS in development and genome stability, as well as the cellular and animal models used to study their pathogenic mechanisms. The article highlights the complex interplay between TDP-43 and FUS/TLS in neurodegeneration and the need for further research to understand their precise roles in RNA processing and neurodegenerative diseases.The article reviews the emerging roles of TDP-43 and FUS/TLS in RNA processing and neurodegeneration. TDP-43 and FUS/TLS are RNA/DNA-binding proteins that have been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The identification of mutations in these proteins has shifted the understanding of ALS and FTLD pathogenesis. TDP-43 mislocalization and aggregation are common pathological hallmarks in ALS and FTLD, with 38 dominant mutations identified in TDP-43 and 30 in FUS/TLS. These mutations are associated with both familial and sporadic forms of ALS and FTLD. The article discusses the biochemical and pathological characteristics of TDP-43 and FUS/TLS proteinopathies, including their involvement in multiple steps of RNA processing, transcription regulation, splicing, microRNA processing, and cytosolic roles in RNA subcellular localization, translation, and decay. It also explores the roles of TDP-43 and FUS/TLS in development and genome stability, as well as the cellular and animal models used to study their pathogenic mechanisms. The article highlights the complex interplay between TDP-43 and FUS/TLS in neurodegeneration and the need for further research to understand their precise roles in RNA processing and neurodegenerative diseases.