The biochemical properties of the signal-induced multifunctional transcription factor II-I (TFII-I) indicate that it is involved in a variety of gene regulatory processes. Although gene ablation in murine models and cell-based assays show that it is encoded by an essential gene, GTF2I/Gtf2i, its physiologic role in human disorders was relatively unknown until recently. Novel studies show that it is involved in an array of human diseases including neurocognitive disorders, systemic lupus erythematosus (SLE), and cancer. Here I bring together these diverse observations to illustrate its multiple pathophysiologic functions and further conjecture on how these could be related to its known biochemical properties. I expect that a better understanding of these 'structure-function' relationships would lead to future diagnostic and/or therapeutic potential.