The major mRNA decay pathway in Saccharomyces cerevisiae occurs through deadenylation, decapping, and 5' to 3' degradation of the mRNA. Decapping is a critical control point in this decay pathway. Two proteins, Dcp1p and Dcp2p, are required for mRNA decapping in vivo and for the production of active decapping enzyme. To understand the relationship between Dcp1p and Dcp2p, a combination of both genetic and biochemical approaches were used. First, we demonstrated that when Dcp1p is biochemically separated from Dcp2p, Dcp1p was active for decapping. This observation confirmed that Dcp1p is the decapping enzyme and indicated that Dcp2p functions to allow the production of active Dcp1p. We also identified two related proteins that stimulate decapping, Edc1p and Edc2p (Enhancer of mRNA DeCapping). Overexpression of the EDC1 and EDC2 genes suppressed conditional alleles of dcp1 and dcp2, respectively. Moreover, when mRNA decapping was compromised, deletion of the EDC1 and/or EDC2 genes caused significant mRNA decay defects. The Edc1p also co-immunoprecipitated with Dcp1p and Dcp2p. These results indicated that Edc1p and Edc2p interact with the decapping proteins and function to enhance the decapping rate.