The transduction of electric fields into protein motion plays an essential role in the generation and propagation of cellular signals. Voltage-sensing domains (VSD) in ion channels and enzymes carry out these functions through reorientations of discrete gating charges in the S4 helix. The voltage sensitive phosphatase from C. intestinalis (Ci-VSP) is controlled by a standard VSD with high sequence similarity to the S1-S4 segments found in Na+ and K+ channels. To address some of the fundamental questions regarding how membrane proteins sense transmembrane voltages, we have pursued structural and biophysical information on Ci-VSP's isolated VSD, under conditions that stabilize the Up and the Down conformations. An overview of the conformational transitions in VSDs from Ci-VSP and the potassium channel KvAP is provided on the basis of combined X-ray crystallography, spectroscopy and electrophysiology analyses. These results provide an explicit mechanism for voltage sensing and set the basis for electromechanical coupling in voltage-dependent enzymes and ion channels.