MAPKs are members of a three-kinase phosphorelay system composed of the MAPK, MAPK kinase (MKK) and MAPK kinase kinase (MKKK). MKKKs phosphorylate and activate MKKs, which in turn phosphorylate and activate MAPKs. Scaffolding proteins organize MKK-MAPK complexes for activation by specific MKKKs and do so in specific locations in the cell. It is the MKKK associated with the scaffolded complex that provides selectivity for activation by upstream stimuli including GTPases, additional kinases and receptors. The demonstration that specific MKKKs also exert control over gene expression by regulating the repertoire of required transcriptional machinery is a newly recognized function for MKKKs. Appreciation of MKKKs as signaling hubs for selectively integrating different upstream stimuli into the control of MAPK networks, and the ability of MKKKs to function as master planners of the transcription factor machinery suggest that MKKK inhibitors will provide selective therapeutic intervention of stimulus-specific MAPK responses.