Extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are important members of the mitogen-activated protein kinase (MAPK) family and have emerged as key effector targets of activation by seven-transmembrane-spanning (G-protein-coupled) receptors (7TMRs). Regulation of ERK by 7TMRs is highly complex and dependent on cell type. Numerous studies have linked specific G protein pathways to ERK activation, but recent evidence suggests that some 7TMR-linked ERK signalling pathways might not be exclusively mediated by G proteins. In addition, the emergence of an ‘inside-out' model for receptor tyrosine kinase (RTK) ‘transactivation' by 7TMRs has enhanced our understanding of the ERK signalling system and further underscores the complexity of mitogenic regulation by 7TMRs.