Stressful conditions can damage or kill cells. Consequently, the cell has devised stress response mechanisms to protect the cell. The formation of reversible protein-RNA granules called stress granules protect mRNAs during this time. Aberrant stress granule function is associated with neurodegenerative diseases in particular the motor neuron disease amyotrophic lateral sclerosis (ALS) and the dementia frontotemporal lobar degeneration (FTLD). TIA-1 is a nucleo-cytoplasmic RNA-binding protein that sequesters target RNA into stress granules under conditions of cellular stress. Stress granule formation by TIA-1 is understood to be initiated via RNA binding and also depends upon self-association of its prion-like domain that facilitates liquid-liquid phase separation. Here we explore the molecular mechanism underlying this transition. We have investigated the self-associating properties of full-length TIA-1 in vitro using thioflavin T, EM DIC microscopy and SAXS. We have shown that target oligonucleotide (RNA or DNA), but not double stranded or non-specific oligonucleotide, greatly enhances the self-association kinetics of TIA-1 via the localisation of TIA-1 at multisite target RNA that seeds TIA-1 self-association. Conversely, excess target oligonucleotide reduces TIA-1 self-association. TIA-1 self-association via RNA interactions readily progresses to the formation of fibrillar structures, consistent with our understanding of the pathogenic outcome of stress granule dysregulation.