The G2‐M transition of the cell cycle requires the activation of members of the Cdc25 dual specificity phosphatase family. Using Xenopus oocyte maturation as a model system, we have previously shown that chelation of transition metals blocks meiosis progression by inhibiting Cdc25C activation. Here, using approaches that allow for the isolation of very pure and active recombinant Cdc25C, we show that Cdc25C does not bind zinc as previously reported. Additionally, we show that mutants in the disordered C‐terminal end of Cdc25C are poor initiators of meiosis, likely due to their inability to localize to the proper sub‐cellular location. We further demonstrate that the transition metal chelator, TPEN, acts on or upstream of polo‐like kinases in the oocyte to block meiosis progression. Together our results provide novel insights into Cdc25C structure‐function relationship and the role of transition metals in regulating meiosis. Transition metals are required for meiosis progression in the frog oocyte. This requirement is upstream of the activation of the dual specificity phosphatase Cdc25C, which does not bind zinc, but requires specific residues in its C‐terminus for proper function.