The MAP kinases, extracellular-regulated protein kinases 1 & 2 (ERK1/2), are important drug targets for cancers caused by oncogenic mutations in RAS and B-RAF. Preclinical studies show that cells from metastatic cancers with acquired resistance to RAF and MKK inhibitors can be effectively killed using small molecule inhibitors of ERK, some of which are in early stage clinical trials. An important unsolved question is: How is ERK2 activated by dual phosphorylation at Thr and Tyr residues, both catalyzed by MKK1/2? Using hydrogen exchange mass spectrometry and NMR relaxation dispersion experiments, we discovered that the activation of ERK2 involves the release of protein motions, leading to global exchange between conformational states which we believe function to enable productive nucleotide binding. An intriguing possibility is that these phosphorylation-regulated dynamics may be coupled to steps in catalytic turnover. Importantly, high affinity ERK inhibitors, which are effective towards cells with acquired resistance, show properties of conformation selection in a manner correlating with slow dissociation. Our findings suggest that the regulated dynamics of ERK2 are exploited by these inhibitors to improve their kinetic properties and efficacy.