The decay of mRNA occurs in specific loci in cells termed P-bodies (mRNA-processing bodies). The process involves an extensive number of proteins, including decapping enzymes for the removal of the cap structure found at the 5’ end of mRNA. The Dcp2 decapping enzymes hydrolyze capped mRNA to generate ^m7GDP and a monophosphorylated RNA product that will be further degraded by exonucleases. These enzymes are characterized by a conserved 23-aa catalytic Nudix motif. Furthermore, orthologs of Dcp2 have been found in various divergent organisms throughout the tree of life, including humans, yeasts, plants and viruses. In this review, we will discuss the recent advances made in the characterization of Dcp2-like decapping enzymes, including their structure, cofactors, and proposed mechanisms.