A detailed exploration of the three proposed mechanisms (associative, dissociative, and interchange) for the activation of Grubbs-Hoveyda-type precatalysts is performed, using DFT (B3LYP) calculations. The effects induced by the nature of the reacting alkene, the bulk of the chelating alkoxy group, and the presence of substituents in the Hoveyda ligand are taken into account. Results show that, while the associative mechanism has always high energy barriers, neither the dissociative nor the interchange mechanism can be ruled out for the first step of the activation process. In fact, the preference for one or the other mechanism seems to be influenced, to a large extent, by the nature of the chelating alkoxy group in such a way that small OR groups tend to favor the interchange pathway. Moreover, for all considered Grubbs-Hoveyda-type precatalysts, the highest transition structure corresponds to the Hoveyda ligand decoordination at the end of the cross-metathesis process. It is worth noting that this is observed regardless of the initial alkene coordination pathway (dissociative or interchange), precursor nature, and substrate and, thus, the rate-determining transition structure in all considered cases is the final alkene decoordination process. In contrast, the highest transition structure for the activation process of the phosphine-containing complexes is the initial phosphine dissociation, for which the reacting alkene is not yet involved. Overall, although the interchange mechanism may also have a role, the present calculations show that the different sign of the experimentally measured activation entropies is more likely associated with a change in the nature of the rate-determining transition structure rather than in a change of the nature of the elementary steps. © 2012 American Chemical Society.