Map kinases are drug targets for autoimmune disease, cancer, and apoptosis- related diseases. Drug discovery efforts have developed MAP kinase inhibitors directed toward the ATP binding site and neighboring “DFG-out” site, both of which are targets for inhibitors of other protein kinases. On the other hand, MAP kinases have unique substrate and small molecule binding sites that could serve as inhibition sites. The substrate and processing enzyme D-motif binding site is present in all MAP kinases, and has many features of a good small molecule binding site. Further, the MAP kinase p38α has a binding site near its C-terminus discovered in crystallographic studies. Finally, the MAP kinases ERK2 and p38α have a second substrate binding site, the FXFP binding site that is exposed in active ERK2 and the D-motif peptide induced conformation of MAP kinases. Crystallographic evidence of these latter two binding sites is presented.