Mexiletine's actions on voltage-clamped sodium channels of frog myelinated nerve and skeletal muscle are described. Mexiletine blocks half the sodium channels (infrequent depolarizations) of single myelinated nerves at a 83 micro M concentration while only 26 micro M is required to do the same in skeletal muscle preparations where similar vaseline-gap techniques are utilized. Mexiletine's potency for block of sodium current in nerve is clearly related to its lipid distribution characteristics given proper consideration of the drug class to which it belongs. Hyperpolarizing prepulses, which are typically used to remove normal sodium inactivation, appear to reduce drug blocking potency suggesting that noninactive channels have a considerably lower affinity for the drug than do inactive channels. Direct evidence supporting selective drug block of inactive channels is also given. In addition the effects of this drug on sodium channels of guinea pig papillary muscle have been studied using measurements of maximum upstroke velocity of intracellularly recorded action potentials. In these myocardial studies 5 to 20 micro M mexiletine depressed upstroke velocity of papillary muscle action potentials in a frequency-dependent fashion. No basal (nonfrequency-dependent) block was observed in heart at these therapeutic concentrations of mexiletine. comparisons are made between skeletal and cardiac muscle effects of mexiletine, especially relating to the important role played by sodium channel inactivation.