Smooth muscle tissues exhibit a marked plasticity in their response to mechanical forces as well as to neural, endocrine and metabolic stimuli. This enables the tissues to rapidly adapt to differing functional demands. Adult smooth muscle cells are not terminally differentiated, and hence are able to revert to a synthetic phenotype with reduced contractility but high capacity for proliferation, migration and synthesis of extracellular matrix. In the vascular system, such phenotype shifts typically occur in response to endothelial injury, inflammation or lipid infiltration, leading to development of atherosclerotic plaques or of neointima formation following vascular surgery. Hypertension induces a different form of growth process, where cells are maintained in contractile phenotype and grow primarily by hypertrophy with much lower proliferation rates than in the synthetic phenotype. The signal mechanisms regulating growth processes must therefore be able to distinguish these different conditions, and much evidence indicates that stretch of the vascular wall has a key role, likely involving integrins and focal adhesion signalling as well as activation of G-protein coupled receptors. Overall protein synthesis and proliferation are stimulated by growth factor signalling and activation of the MAP kinase cascade, but is also rapidly activated by stretch. Stretch is furthermore able to increase the intracellular Ca2+ concentration, with downstream effects on gene expression depending on the mode of Ca2+ influx, via voltage-dependent and -independent pathways (Ren et al. 2010). In many vascular tissues, phenotype shift has been shown to be associated with a decrease of voltage-dependent L-type Ca2+ channels and an increase of non-voltage dependent, particularly store-operated, channels (Kumar et al. 2006). The synthesis of most contractile and cytoskeletal proteins, marking the contractile smooth muscle phenotype, is regulated by serum response factor (SRF) in concert with the coactivators myocardin and myocardin-related transcription factors (MRTFs). These factors bind to multiple conserved sites (CArG boxes) in the promoter regions of the smooth muscle genes. Growth factor stimulation causes displacement of myocardin from SRF and thus competes with differentiation. While myocardin is localised to the nucleus, MRTF is bound to monomeric G-actin in the cytoplasm and translocates to the nucleus when released from this binding. Polymerisation to filamentous F-actin reduces the cytoplasmic G-actin concentration and promotes nuclear translocation of MRTF. Stretch of vascular smooth muscle increases actin polymerisation via activation of RhoA and stimulates synthesis of smooth muscle proteins, thus stabilising the contractile phenotype. However, a further effector potentially regulated by RhoA is myocardin, which in contrast to smooth muscle markers is not dependent on SRF but is a transcriptional target of myocyte enhancer factor-2 (MEF2; Creemers et al. 2006). RhoA stimulation by membrane depolarization increases myocardin mRNA, which is mediated via activation of Rho-associated kinase and MEF2 transcription (Ren et al. 2010). Stretch increases myocardin mRNA as well and hence seems to stabilise the contractile phenotype via at least two Rho-dependent mechanisms, myocardin expression and MRTF translocation. MEF2, in addition to its possible role in smooth muscle differentiation via Rho activation and voltage-dependent Ca2+ influx, is well established to be a mediator of growth factor signalling. Repression of MEF2 activity by binding to histone deacetylase 4 (HDAC4) is released by phosphorylation of HDAC4, requiring Ca2+/calmodulin-dependent kinase II (CaMK II; Li et al. 2010). This activation mechanism is linked to store-operated Ca2+ influx (Ren et al. 2010), and hence the balance between smooth muscle growth and differentiation is regulated by multiple interacting mechanisms involving stretch as well as growth factors and Ca2+ influx pathways. Integration of these pathways enables diverse phenotype regulation in response to external stimuli and muscle activity, including simultaneous growth and differentiation in stretch-induced hypertrophy.