Scaffolding proteins add a new layer of complexity to the dynamics of cell 
signaling. Above their basic function to bring several components of a signaling 
pathway together, recent experimental research has found that scaffolds 
influence signaling in a much more complex way: scaffolds can exert some 
catalytic function, influence signaling by allosteric mechanisms, are 
feedback-regulated, localize signaling activity to distinct regions of the cell 
or increase pathway fidelity. Here we review experimental and theoretical 
approaches that address the function of two MAPK scaffolds, Ste5, a scaffold of 
the yeast mating pathway and KSR1/2, a scaffold of the classical mammalian MAPK 
signaling pathway. For the yeast scaffold Ste5, detailed mechanistic models have 
been valuable for the understanding of its function. For scaffolds in mammalian 
signaling, however, models have been rather generic and sketchy. For example, 
these models predicted narrow optimal scaffold concentrations, but when 
revisiting these models by assuming typical concentrations, rather a range of 
scaffold levels optimally supports signaling. Thus, more realistic models are 
needed to understand the role of scaffolds in mammalian signal transduction, 
which opens a big opportunity for systems biology.