RNA decay plays a crucial role in post-transcriptional regulation of gene expression. Work conducted over the last decades has defined the major mRNA decay pathways, as well as enzymes and their cofactors responsible for these processes. In contrast, our knowledge of the mechanisms of degradation of non-protein coding RNA species is more fragmentary. This review is focused on the cytoplasmic pathways of mRNA and ncRNA degradation in eukaryotes. The major 3' to 5' and 5' to 3' mRNA decay pathways are described with emphasis on the mechanisms of their activation by the deprotection of RNA ends. More recently discovered 3'-end modifications such as uridylation, and their relevance to cytoplasmic mRNA decay in various model organisms, are also discussed. Finally, we provide up-to-date findings concerning various pathways of non-coding RNA decay in the cytoplasm.