Voltage clamp experiments were carried out on Rana catesbiana nodes of Ranvier in order to test predictions regarding the relationship between local anesthetic lipid solubility and the rate of development of and recovery from frequency-dependent increments of sodium channel block. Contrary to expectations, the drugs of greater lipid solubility than lidocaine showed slower rates of development of frequency-dependent block and, in addition, induced longer rather than shorter memories for recent frequency-depent increments in channel block. Relaxation time constants for bupivacaine (50 micrometer), etidocaine (15 micrometer) and tetracaine (0.7 micrometer) measured 50, 8 and 8 sec, respectively, compared to shorter time constant of 2 sec for lidocaine (250 micrometer). Rate constants were calculated for binding to channels in both open and closed states. Open channels displayed a 130- to 6000-fold greater affinity for the local anesthetics than did closed channels, verifying an important feature of the "modulated receptor" hypothesis. In addition, binding to closed channels was enhanced by holding the membrane at more depolarizing potentials, which favored the development of inactive channel states. The exceptionally large binding constants of lidocaine for interactions with both closed and open channels cannot be attributed to its lipid solubility characteristics alone.