A large number of human diseases are caused by expansion of repeat sequences - typically trinucleotide repeats - within the respective disease genes. The abnormally expanded sequence can lead to a variety of effects on the gene: sometimes the gene is silenced, but in many cases the expanded repeat sequences confer toxicity to the mRNA and, in the case of polyglutamine diseases, to the encoded protein. This article highlights mechanisms by which the mRNAs with abnormally expanded repeats can confer toxicity leading to neuronal dysfunction and loss. Greater understanding of these mechanisms will provide the foundation for therapeutic advances for this set of human disorders.