High-voltage-activated calcium (CaV) channels convert electrical signals into Ca2+ ion influx to trigger biological responses in excitable cells. CaV channel dysfunction underlies many cardiovascular and neurological diseases, from cardiac arrhythmias to autism. Modulation of CaV channels by intracellular signaling proteins, Ca2+ ions and various small molecules is a powerful method to regulate physiology and is therapeutic for myriad disease conditions. I will discuss CaV channel engineering approaches that we have used to gain insights into the structure-function mechanisms of these vital proteins, to probe their physiological roles, and to develop novel genetically-encoded molecules that modulate their activity.