Proteins are often referred to in accordance with the activity with which they were first associated or the organelle in which they were initially identified. However, a variety of nuclear factors act in multiple molecular reactions occurring simultaneously within the nucleus. This review describes the functions of the nuclear factors PSF (polypyrimidine tract-binding protein-associated splicing factor) and p54(nrb)/NonO. PSF was initially termed a splicing factor due to its association with the second step of pre-mRNA splicing while p54(nrb)/NonO was thought to participate in transcriptional regulation. Recent evidence shows that the simplistic categorization of PSF and its homolog p54(nrb)/NonO to any single nuclear activity is not possible and in fact these proteins exhibit multi-functional characteristics in a variety of nuclear processes.