This talk presents an overview on recent experimental and computational studies on the off‑cycle reactions of palladium- and nickel-catalyzed cross-couplings.1-5 Several reactions entering and leaving the catalytic cycle have been characterized, including precatalyst activation by an H-shift mechanism and deactivation by comproportionation into dimeric species. The molecular-level understanding of off-cycle reactions has enabled new catalyst design strategies, including the stereoelectronic fine-tuning of the ligands aimed at maximizing the activation of the precatalyst meanwhile preventing its degradation. Despite several challenges, which concern both experiments (e.g. isolation and characterization of transient species) and computations (e.g. comprehensive mapping of the potential energy surface), this approach has already been applied with success in the optimization of popular catalytic platforms, including NHC–Pd–allyl precatalysts, and shows promise for the development of highly active and robust catalysts based on nickel.