DNA and RNA stimulate the mammalian innate immune system by triggering a variety of sensors, including Toll-like receptors (TLRs). TLR9 signals upon exposure to DNA, while TLR3, TLR7 and TLR8 respond to RNA. Most DNA and RNA from natural sources contain modified nucleosides. Methylation of CpG motifs in DNA blocks TLR9 signaling. The question of whether an analogous effect can be attributed to nucleoside modifications in RNA has only recently been addressed. This review characterizes a few naturally occurring nucleoside modifications of RNA and their influence on the capacity of RNA to activate immune cells and TLRs. RNAs containing modified nucleosides, and thus lacking immune-activating properties, have potential importance in clinical applications.