Voltage-gated ion channels (VGICs) of excitable tissues are emerging as targets likely involved in both the therapeutic and toxic effects of inhaled and intravenous general anesthetics. Whereas sevoflurane and propofol inhibit voltage-gated Na+ channels (Navs), sevoflurane potentiates certain voltage-gated K+ channels (Kvs). The combination of these effects would dampen neural excitability and, therefore, might contribute to the clinical endpoints of general anesthesia. As the body of work regarding the interaction of general anesthetics with VGICs continues to grow, a multidisciplinary approach involving functional, biochemical, structural, and computational techniques, many of which are detailed in other chapters, has increasingly become necessary to solve the molecular mechanism of general anesthetic action on VGICs. Here, we focus on electrophysiological and modeling approaches and methodologies to describe how our work has elucidated the biophysical basis of the inhibition Navs by propofol and the potentiation of Kvs by sevoflurane.