The complexity of the transmetalation step in a Pd-catalyzed Negishi reaction has been investigated by combining experiment and theoretical calculations. The reaction between trans-[PdMeCl(PMePh2)2] and ZnMe2 in THF as solvent was analyzed. The results reveal some unexpected and relevant mechanistic aspects not observed for ZnMeCl as nucleophile. The operative reaction mechanism is not the same when the reaction is carried out in the presence or in the absence of an excess of phosphine in the medium. In the absence of added phosphine an ionic intermediate with THF as ligand ([PdMe(PMePh2)2(THF)]+) opens ionic transmetalation pathways. In contrast, an excess of phosphine retards the reaction because of the formation of a very stable cationic complex with three phosphines ([PdMe(PMePh2)3]+) that sequesters the catalyst. These ionic intermediates had never been observed or proposed in palladium Negishi systems and warn on the possible detrimental effect of an excess of good ligand (as PMePh2) for the process. In contrast, the ionic pathways via cationic complexes with one solvent (or a weak ligand) can be noticeably faster and provide a more rapid reaction than the concerted pathways via neutral intermediates. Theoretical calculations on the real molecules reproduce well the experimental rate trends observed for the different mechanistic pathways. © 2011 American Chemical Society.