Vascular smooth muscle (VSM) undergoes a phenotypic switch in response to injury, a process that contributes to pathophysiological vascular wall remodelling. VSM phenotype switching is a consequence of changes in gene expression, including an array of ion channels and pumps affecting spatiotemporal features of intracellular Ca(2+) signals. Ca(2+) signalling promotes vascular wall remodelling by regulating cell proliferation, motility, and/or VSM gene transcription, although the mechanisms are not clear. In this review, the functions of multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in VSM phenotype switching and synthetic phenotype function are considered. CaMKII isozymes have complex structural and autoregulatory properties. Vascular injury in vivo results in rapid changes in CaMKII isoform expression with reduced expression of CaMKIIγ and upregulation of CaMKIIδ in medial wall VSM. SiRNA-mediated suppression of CaMKIIδ or gene deletion attenuates VSM proliferation and consequent neointimal formation. In vitro studies support functions for CaMKII in the regulation of cell proliferation, motility and gene expression via phosphorylation of CREB1 and HDACIIa/MEF2 complexes. These studies support the concept, and provide potential mechanisms, whereby Ca(2+) signalling through CaMKIIδ promotes VSM phenotype transitions and vascular remodelling.