Neointimal hyperplasia and atherosclerosis are cardiovascular abnormalities resulting in heart attacks and strokes – major causes of death and disability, particularly in societies with a western-style diet. Both are contributed to significantly by a phase of enhanced cell cycle activity, proliferation and migration of vascular smooth muscle cells. The lecture will describe how this activity is associated with a switch in the types of ion channel controlling trans-membrane ion transport. One striking feature is the de novo expression of the KCa3.1 (IKCa) potassium channel. This seems functionally important because an inhibitor of KCa3.1 suppresses neointimal hyperplasia in segments of human saphenous vein (Cheong et al 2005, Mol Cell 20, 45-52). Our data also show that down-regulation of the repressive REST transcription factor, which occurs in smooth muscle cells of the neointima, is a factor enabling expression of the gene encoding KCa3.1. With the discovery of REST in smooth muscle cells we find it has wider implications, including having effects on other potassium channel genes. Concomitant with the gain of KCa3.1 there is loss of the L-type voltage-dependent calcium channel and increased expression, and function, of the voltage-independent TRPC1 calcium-permeable channel. Antibody targeting TRPC1 suppresses neointimal hyperplasia in saphenous vein (Kumar et al 2006 Circ Res 98, 557-563), consistent with a hypothesis whereby hyperpolarisation driven by potassium channel activity (e.g. KCa3.1) enhances calcium entry through TRP channels, which in turn facilitates calcium-dependent processes of the cell cycle and gene transcription. We have also found evidence for roles of ion channels in the migration of smooth muscle cells, showing that antibody targeting TRPC5 and dominant negative mutant TRPC5 inhibit migration evoked by the key phospholipid signalling molecule sphingosine-1-phosphate (Xu et al 2006 Circ Res 98, 1381-1389). TRPC5 is a polymodal channel, responding also to lysophosphatidylcholine (Flemming et al 2006 J Biol Chem 281, 4977-4982) a dominant constituent of oxidised low-density lipoprotein. In summary, we hypothesise that ion channel switching is an important factor in vascular smooth muscle cell migration and proliferation, contributing to progression of unwanted vascular adaptation such as neointimal hyperplasia. Sensitivity of some of these ion channels to key lipid factors may mean that the processes also make adverse contributions to atherosclerosis.