Maintenance of normal peripheral vascular resistance and perfusion of vital organs depends on the structure and contractile function of small arteries within the vasculature, and vasoconstrictor hormone regulation of small artery contractility is an important determinant of vascular resistance and blood pressure. Changes in these properties of small blood vessels lead to cardiovascular disease. For instance, in response to prolonged stress e.g. maintained high blood pressure, smooth muscle cells within small arteries exhibit exaggerated contractility and remodelling of the vessel wall, as seen in hypertension or migration and proliferation as in arteriosclerosis. An important role for the actin cytoskeleton in cellular responses; contraction, proliferation and migration, is now recognised. It is also established that a dynamic cytoskeleton is necessary for smooth muscle cell migration, and recent evidence implicates the reorganisation of the actin cytoskeleton and its interaction with the cellular contractile machinery as essential for smooth muscle contraction and relaxation. Two distinct pathways regulate cytoskeletal reorganisation in response to agonists: p38 mitogen activated protein kinase (MAPK) and nonreceptor tyrosine kinases such as Src family, p125 focal adhesion kinase (p125FAK), and proline-rich tyrosine kinase-2 (PYK2). p38 MAPK regulates the actin cytoskeleton through the small heat shock protein 27 (Hsp27). By binding to and capping actin filaments, Hsp27 inhibits F-actin polymerisation. This property of Hsp27 is a function of its phosphorylation state such that phosphorylated Hsp27 does not bind to actin allowing reorganisation of the cytoskeleton. Nonreceptor tyrosine kinases regulate the actin cytoskeleton through the tyrosine phosphorylation of cytoskeletal regulatory proteins, including adaptor proteins such as paxillin and its homologue hydrogen peroxide-inducible clone-5 (Hic-5). G protein-coupled receptor agonists activate nonreceptor tyrosine kinases, and in airway and vascular smooth muscle tissues, the tyrosine phosphorylation of paxillin and Hic-5 respectively, is associated with force generation. Although Hic-5 is a homologue of paxillin, unlike the latter it is not activated by integrins or phosphorylated by p125FAK. However, PYK2, a calcium-dependent homologue of p125FAK, does phosphorylate Hic-5 suggesting different cellular functions for the two adaptor proteins. Hic-5 has been identified in vascular smooth muscle tissues, and is phosphorylated by PYK2 when stimulated by noradrenaline. Furthermore, through its ability to interact with Hsp27, Hic-5 plays an important role in the regulation of smooth muscle actin dynamics. This talk will describe the complex molecular mechanisms that regulate actin cytoskeleton reorganisation in vascular smooth muscle, concentrating on tyrosine kinases and their downstream substrates, with a particular emphasis on their role in contractility.