Gene regulation by short RNAs is a ubiquitous and important mode of control. MicroRNAs are short, single-strand RNAs that bind with partial complementarity to the 3' untranslated region of several genes to silence their expression. This expanding class of endogenous short RNAs are evolutionarily conserved and participate in control of development and cell-specific gene function. Several of these microRNAs have been cloned uniquely from mammalian lymphocytes suggesting specialized roles in lymphocyte development and function. In addition, several genes linked to RNAi in lower eukaryotes have mammalian homologs with specialized roles in adaptive immunity. For example, in worms, the nonsense-mediated decay (NMD) and RNAi pathways appear to be intricately linked. NMD plays a key role in regulating antigen-receptor expression in lymphocytes and there are mammalian homologs for factors identified in worms that appear to be common in both RNAi and NMD pathways. On the other hand, RNA editing and RNAi have an inverse relationship and RNA editing has an important role in viral immunity. These observations indicate unique roles for dsRNAs in the mammalian immune system.