Voltage-gated ion channels shape electrical signaling in the excitable cells of nerve and muscle. Sodium (NaV) and calcium channels (CaV) drive membrane depolarization and activate second messenger pathways via gated cellular entry of their namesake ions. In skeletal and cardiac cells, CaV channels trigger muscle contraction. Voltage-gated potassium channels (KV) allow the release of potassium ions from within the cell to drive membrane repolarization. In concert, these channels provide the molecular foundation for thought, perception, and contraction. High-resolution protein structures of human voltage-gated channels are now providing the first glimpses of the types of poses they may adopt in cellular environments. However, understanding the ultimate link between how these proteins look and how they support physiological mechanisms is a major challenge that will require innovative approaches. For one, transmembrane voltage is absent in a structural experiment thus depicting voltage-gated channels in an essentially non-physiological environment. We are therefore developing photochemical `stapling' approaches to covalently trap high-value protein conformations in live cell membranes prior to purification for structural determination. Further, we have begun to identify mechanisms of channel function by introducing modified chemistries at the peptide backbone in the transmembrane segments that form voltage-sensors and channel gates. In cellular settings, ion channels are also critical amplifiers of transduction pathways. During the fight-or-fight response, for instance, the near instantaneous phosphorylation of CaV1.2 channels results in faster and sustained channel opening, leading to a more forceful and rapid heart rate. Yet the absolute speed and complexity of the process is a challenge to experimentally parse individual molecular events that result in channel gating modifications. We describe newly validated methods that enable light controlled, site-specific phosp