Several neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA) are caused by non‐coding nucleotide repeat expansions. Different pathogenic mechanisms may underlie these non‐coding repeat expansion disorders. While gain‐of‐function mechanisms, such as toxicity associated with expression of repeat RNA or toxicity associated with repeat‐associated non‐ATG (RAN) products, are most frequently connected with these disorders, loss‐of‐function mechanisms have also been implicated. We review the different pathways that have been linked to non‐coding repeat expansion disorders such as C9ORF72‐linked ALS/frontotemporal dementia (FTD), myotonic dystrophy, fragile X tremor/ataxia syndrome (FXTAS), SCA, and Huntington's disease‐like 2. We discuss modes of RNA toxicity focusing on the identity and the interacting partners of the toxic RNA species. Using the C9ORF72 ALS/FTD paradigm, we further explore the efforts and different methods used to disentangle RNA vs. RAN toxicity. Overall, we conclude that there is ample evidence for a role of RNA toxicity in non‐coding repeat expansion diseases.