Nucleotide-repeat expansions (NREs) underlie a heterogeneous group of neurodegenerative and neuromuscular disorders for which there are currently no effective therapies. Recently, it was discovered that NREs in mRNA can support translation initiation in the absence of an AUG start codon across a wide variety of sequence contexts, and that the products of these atypical translation initiation events contribute to neuronal toxicity. The mechanism of this process, known as repeat-associated, non-AUG (RAN) translation, remains unclear. RAN translation at two loci at least—CGG repeats in FMR1 [(associated with Fragile X-associated tremor/ataxia syndrome (FXTAS)] and G4C2 repeats in C9ORF72 [(associated with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)]—generates homopolymeric and dipeptide-repeat (DPR) proteins that elicit toxicity through a variety of mechanisms. Additional research into which protein factors [particularly eukaryotic initiation factors (eIFs) and other known regulators of translation] mediate or modulate RAN translation would prove advantageous, both in understanding this odd biological phenomenon and identifying potential targets for therapeutic intervention.