Compositions and methods relating to immunostimulatory RNA oligomers areprovided. The immunostimulatory RNA molecules are believed to representnatural ligands of one or more Toll-like receptors, including Toll-likereceptor 7 (TLR7) and Toll-like receptor 8 (TLR8). The compositions andmethods are useful for stimulating immune activation. Methods useful forscreening candidate immunostimulatory compounds are also provided.