The chemistry and the physics of voltage sensitive dyes should be understood and appreciated as a prerequisite for their optimal application to problems in neuroscience. This talk will provide a basic understanding of the properties of the large variety of available organic voltage sensitive dyes. The mechanisms by which the dyes respond to voltage guides the best set up of the optics for recording or imaging electrophysiological activity. The physical and chemical properties of the dyes can be tuned to optimize delivery to and staining of the cells in different experimental preparations. High resolution microscope imaging, including confocal and non-linear optical microscopy, are being used in conjunction with the voltage sensitive dyes to map electrical activity in both space and time; these optical approaches will be briefly surveyed. Applications of the dyes to optical imaging of electrical activity in individual cells and tissues will be presented to illustrate the range of problems that can be tackled with this technology. Results from microscope imaging experiments also provide data for mathematical models of the physiology. I will briefly introduce the Virtual Cell, a software system for reaction-diffusion modeling that has been used to simulate neuronal cell biology. (supported by USPHS NIH grants: U54 RR022232, R01 EB001963 and P41 RR13186)