The unphosphorylated STATs, known as U-STATs, play important roles in gene expression by different mechanisms than phosphorylated STATs. When activated by cytokines or growth factors, U-STATs like STAT1 and STAT3 drive gene expression in response to interferons or IL-6. These U-STATs are specific targets of activated STATs and lead to increased levels of gene expression. This review discusses how U-STATs regulate gene expression differently from phosphorylated STAT dimers.