Within the signalling network of mammalian cells, MAPK-activated protein kinases (MAPKAPKs) have been identified downstream to various MAPKs, such as the classical MAPKs, ERK1/2, the stress-activated p38 MAPKs and the atypical MAPKs ERK3/4/5. Here, the current understanding of the specificity of MAPK to MAPKAPK signalling, the underlying mechanisms of protein-protein-interaction and the effects on subcellular localisation are reviewed. It is demonstrated that specificity in this signalling section is maintained by protein domain interactions and by regulated subcellular localisation. These mechanisms enable specific MAPK pathways to act independently via specific MAPKAPKs but also allow different MAPK pathways to cooperate in downstream signalling in a coordinated fashion.