RNA interference (RNAi) is an ancient and evolutionarily conserved process. In some eukaryotes, RNAi silences parasitic genetic elements. In plants, RNAi serves as an immune system against RNA viruses and transgenes and in worms, RNAi silences transposons. In mammals, RNAi has yet unknown functions. However, emerging roles for short RNAs and the factors that interact with them in other eukaryotes include chromatin modification, DNA deletion and DNA methylation, which may provide clues to the roles for short RNA function in mammals. For example, antigen receptor expression in lymphocytes is a highly regulated process and although much is known about chromatin modification and DNA deletion in the immune system, several molecular details of chromatin regulation remain elusive. This review compares emerging roles for short RNA function to processes required for antigen receptor expression in mammalian lymphocytes and predicts that short RNAs direct events required for successful lymphocyte-restricted gene expression.