Voltage-activated sodium (Nav) channels are found throughout the human body where they form the cornerstones of fast electrical signaling by regulating the Na+ permeability of the cell membrane. As such, Nav channels are among the most widely targeted ion channels by both drugs and animal toxins. Their medical relevance is underscored by mutations that underlie debilitating disorders such as epilepsy, muscle weakness, cardiac arrhythmias and pain syndromes. Despite their physiological importance, our understanding of these channels is hampered by a lack of insight into their complex structures and working mechanisms. Rather than existing as independent units, Nav channels are part of a signaling complex that involves auxiliary proteins and membrane lipids. Our goal is to address fundamental questions on the identities of the Nav channel signaling complex components and to resolve their mechanisms of action at the molecular level. To this end, we combine several techniques including molecular biology, electrophysiology, genetics, and biochemistry. Successful completion of these goals will reveal key elements in the Nav channel signaling complex, help define Nav channel function in normal and pathological states, and may offer novel strategies for developing therapeutic drugs.