Export of mRNA from the nucleus is a central process in eukaryotic gene expression that has been implicated in several human diseases. Much of our understanding of how an mRNA is transported to the cytoplasm is derived from studies using yeast and fly models. We present here different mechanisms by which aberrant nuclear retention of mRNA can cause human disease. Emerging evidence that implicates the mRNA export factor GLE1 in two lethal motor neuron disorders is discussed and we highlight surprising links to regulatory mechanisms that were first observed many years ago in yeast. These examples illustrate how model organisms have aided in our elucidation of complex human disorders through analysis of basic cellular processes.