The chemistry and the physics of voltage sensitive dyes (VSDs) should be understood and appreciated as a prerequisite for their optimal application to problems in neuroscience cardiology. This chapter provides a basic understanding of the properties of the large variety of available organic VSDs. 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. The aim of this chapter is to arm the experimentalists who use the dyes with enough information and data to be able to intelligently choose the best dye for their specific requirements.