Voltage-gated calcium (CaV) channels conduct Ca2+ ions into cells in response to depolarization and thereby contribute to regulate diverse biological events in a wide variety of tissues including nerves, glands and muscles. They are responsible for initiation of excitation-contraction and excitation-secretion coupling, and are involved in the regulation of protein phosphorylation and gene transcription, among many other intracellular events. The activity of CaV channels may be regulated by a number of cell surface receptors acting through G proteins as well as by protein phosphorylation and other post-translational modifications. Likewise, it is acknowledged that CaV channels are organized into active signaling platforms depending upon interactions with other molecules including cytoskeletal proteins. Diverse studies have shown that several cytoskeletal components may act as binding partners that help regulate, localize and determine cell surface expression of CaV channel in response to extracellular events. In this review, we survey the interaction of CaV channels with the cytoskeleton and its potential physiological implications.