ERK2 a major effector of the BRAF oncogene is a promiscuous protein kinase that has a strong preference to phosphorylate substrates on Ser-Pro or Thr-Pro motifs. As part of a program to understand the fundamental basis for ERK2 substrate recognition and catalysis we have studied the mechanism by which ERK2 phosphorylates the transcription factor Ets-1 on Thr-38. A feature of the mechanism in the forward direction is a partially rate-limiting product release step, koff = 59 ± 6 s−1, which is significant, because in order to approach maximum efficiency substrates for ERK2 may evolve to ensure that ADP dissociation is rate-limiting. To further understand the mechanism of product release, the binding of the products to ERK2 was assessed and the reaction was examined in the reverse direction. These studies demonstrated that phospho-Ets-1 (p-Ets) binds > 20-fold more tightly to ERK2 than ADP (Kd = 7.3 and 165 μM respectively), revealed that the products exhibit little interaction energetically, while bound to ERK2 and that they can dissociate ERK2 in a random order. The overall equilibrium for the reaction in solution (Keq = 250 M−1) was found to be similar to that while bound to the enzyme (Kint = 525 M−1). To determine what limits koff several pre-steady-state experiments were performed. A catalytic trapping approach furnished a rate-constant of k−ADPa=61±12s−1 for the dissociation of ADP from the abortive ternary complex, ERK2•Ets•ADP. To examine p-Ets dissociation the binding of a fluorescent derivative (p-Ets-F), which binds ERK2 with similar affinity to p-Ets, was examined by stopped-flow kinetics. Using this approach p-Ets-F was found to bind through a single-step mechanism, with the following parameters, k−p-Ets-F = 121 ± 3.8 s−1 and kp-Ets-F = 9.4 ± 0.3 × 106 M−1s−1. Similar results were found in the presence of saturating ADP. These data suggest that koff may be limited by the dissociation of both products and are consistent with the notion that Ets-1 has evolved to be an efficient substrate for ERK2, where ADP release is, at least, partially rate-limiting. A molecular mechanics model of the complex formed between ERK2 and residues 28–138 of Ets-1 provides insight into the role of substrate docking interactions.