Signal-transduction pathways that employ members of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) family of protein Ser/Thr kinases are widely conserved among eukaryotes. The multiplicity of these pathways allows the cell to respond to divergent extracellular stimuli by initiating a broad array of responses ranging from cell growth to apoptosis. ERK/MAPK pathways are comprised of a three-tiered core-signalling module wherein ERK/MAPKs are regulated by MAPK/ERK kinases (MEKs) and MEKs, in turn, are regulated by MAPK kinase kinases (MAPKKKs). The regulation of MAPKKK-->MEK-->ERK/MAPK core-signalling modules by upstream components is poorly understood. Mammalian stress-activated ERK/MAPK pathways have been implicated in numerous important physiological functions, including inflammatory responses and apoptosis. In this review, I will discuss how mammalian stress-regulated ERK/MAPK core-signalling modules couple with members of the SPS1 family of protein kinases and to other upstream elements, and how these stress-regulated pathways influence cell function.