Importin alpha is recognized as a classical nuclear localization signal (cNLS) receptor which mediates nucleocytoplasmic transport. However, it rapidly accumulates in the nucleus in response to cellular stresses, including oxidative stress, causing a blockade of the classical nuclear import pathway. We set out to determine whether importin alpha performs roles in the nucleus after cellular exposure to stresses and discovered that it can act directly to modulate gene expression. With remarkable selectivity, importin alpha2 can access the promoter of Serine/threonine kinase 35 (STK35) and increase the levels of this transcript without requirement for importin beta1. The nuclear accumulation of importin alpha occurred following exposure to stresses which decreased intracellular ATP levels and was followed by non-apoptotic cell death. Hence the gene regulatory function of nuclear importin alpha can direct cell fate. There are now several reports of nuclear-localized importin alpha proteins in diverse cellular states, including cancer. Here we discuss the physiological significance of this novel functional capacity of nuclear importin alpha relationship to a variety of cellular states and fates.