The expansion of unstable microsatellites is the cause of a number of inherited neuromuscular and neurological disorders. While these expanded repeats can be located in either the coding or non-coding regions of genes, toxic RNA transcripts have been primarily implicated in the pathogenesis of non-coding expansion diseases. In this review, we briefly summarize studies which support this RNA-mediated toxicity model for several neurologic disorders and highlight how pathogenic RNAs might negatively impact nervous system functions. However, it is important to note that the distinction between coding versus non-coding regions has become muddled by recent observations that the transcribed portion of the genome or transcriptome is considerably larger than previously appreciated. Thus, we also explore the possibility that a combination of protein and RNA gain-of-function events underlie some microsatellite expansion diseases.