Induction of K(Ca)3.1 (IKCa) potassium channel plays an important role in vascular smooth muscle cell proliferation. Here, we report that the gene encoding K(Ca)3.1 (KCNN4) contains a functional repressor element 1-silencing transcription factor (REST or NRSF) binding site and is repressed by REST. Although not previously associated with vascular smooth muscle cells, REST is present and recruited to the KCNN4 gene in situ. Significantly, expression of REST declines when there is cellular proliferation, showing an inverse relationship with functional K(Ca)3.1. Downregulated REST and upregulated K(Ca)3.1 are also evident in smooth muscle cells of human neointimal hyperplasia grown in organ culture. Furthermore, inhibition of K(Ca)3.1 suppresses neointimal formation, and exogenous REST reduces the functional impact of K(Ca)3.1. Here, we show REST plays a previously unrecognized role as a switch regulating potassium channel expression and consequently the phenotype of vascular smooth muscle cells and human vascular disease.