The Ahern laboratory has a long-standing interest in the pharmacology and function of the voltage-gated ion channels that support electrical signaling in muscle and nerve cells. My laboratory uses chemical biology, protein engineering and biophysics to quantify membrane protein function at high resolution. Our use of genetic code expansion and the design, synthesis and encoding of unnatural amino acids to rescue ion channel genes harboring nonsense (stop) codons, has yielded several interesting recent discoveries: atomic and subatomic details of the function of ion-channel voltage sensors; new protein-chemical interactions relevant for potassium channel gating; H-bond networks that act as molecular timers in potassium channels; and novel mechanisms of drug interactions with ion channels. Data will be discussed related to the role of cation-pi interactions between sodium channel aromatic residues and toxins or therapeutics, and in context of protein structure. Further, data are provided for a mechanistic basis for a therapeutic potassium channel opener.