Sequential activation of kinases (protein kinase cascades) is a general mechanism of signal transduction in many cellular processes. Several related intracellular signaling cascades have been found and characterized in the last 25 years known as mitogen-activated protein kinase (MAPK) signaling cascades. These cascades cooperate in transmitting extracellular signals to their intracellular targets and thus initiate cellular processes such as proliferation, differentiation, development, stress- and inflammatory response, and apoptosis. Each of these signaling cascades consists of protein kinases that sequentially in several steps activate each other by phosphorylation. MAPKs are ubiquitously expressed but regulate a variety of biological responses depending on the cell type. Modulating the function of MAPK pathways by small molecules therefore requires a profound understanding of how MAPKs are integrated in various signaling networks.