ERI-1 is a 3"→5" exoribonuclease with one ERI-1_3"hExo_like domain and a SAP domain. It is conserved in Schizosaccharomyces pombe, Mus musculus, Homo sapiens, Drosophila melanogaster and Arabidopsis thaliana. Although it is conserved in lower fungi, basidiomycetes and Schizosaccharomyces, ERI-1 is lost in filamentous ascomycetes and most budding yeasts. As an important regulator of RNAi, ERI-1 was first identified in a screen for mutants with enhanced sensitivity to dsRNA in Caenorhabditis elegans. It negatively regulates RNAi through degrading siRNA and miRNA. However, the C. elegans ERI-1 can completely bind to the core endogenous RNAi component DCR-1 to inhibit exogenous RNAi and promote specific endogenous siRNA production. The Schizosaccharomyces pombe ERI-1 degrades heterochromatin siRNA and influences the formation of heterochromatin. In addition, ERI-1 plays conservative roles in the 3" terminal modification of 5.8S rRNA. Moreover, the mammalian ERI-1 binds to the ACCCA sequence and excises two unpaired nucleotides, thus participating in the processing and degradation of histone mRNA at the end of S phase. The influenza A virus interacts with ERI-1 to promote viral transcription and proliferation, suggesting that ERI-1 has the potential to be a target of anti-virus drugs. This review summarizes the recent advances of ERI-1 functions in multiple RNA processing pathways, and further discusses the evolutionary loss and medical potentials of ERI-1. Suggestions about future research topics are also provided.