Efficient and specific signaling by mitogen-activated protein kinases (MAPKs) is enhanced by docking sites found on many MAPK substrates and regulators. Here we show that the MAPKs ERK1 and ERK2 form a stable complex (Kd ~ 6 mM) with their substrate the microphthalmia-associated transcription factor (MITF). Complex formation requires an approximately 100-residue domain of MITF that is nearby, but C-terminal to, the MAPK phosphorylation site at Ser73. MITF derivatives lacking this ERK-binding domain do not bind ERK2, and are phosphorylated less efficiently by ERK2. The ERK-binding domain of MITF bears no obvious resemblance to previously characterized MAPK docking motifs; in particular, it does not contain a consensus D-site. Consistent with this, ERK2-MITF binding does not require the integrity of the CD/sevenmaker region of ERK2. Furthermore, D-site peptides, which are able to potently inhibit ERK2-mediated phosphorylation of the Elk-1 transcription factor (IC50=3 mM), are relatively poor inhibitors of ERK2-mediated phosphorylation of MITF, exhibiting greater than 15-fold selectivity for inhibition of Elk-1 vs. MITF. These observations demonstrate substrate-selective kinase inhibition: the possibility that small molecules that target docking interactions may be used to selectively inhibit the phosphorylation of a subset of a kinase’s substrates.