Local anesthetics block impulses in peripheral nerves through the inhibition of voltage-gated sodium channels. However, the effects of local anesthetics may be more complex. It has been reported that local anesthetics not only block the impulses in nerve roots, but could also interact with many membrane phospholipids and proteins, including various receptors, and thereby affect a variety of cellular activities. In fact, there is evidence indicating that local anesthetics could inhibit NMDA-induced glutamatergic transmission in the spinal cord. Therefore, NMDA receptor antagonism of local anesthetics may have the possibility to prevent the patients from developing chronic pain. Furthermore, local anesthetics might have the possibility to prevent cancer cell proliferation like NMDA receptor antagonists. Local anesthetics have also been reported to have an inhibitory effect on other ion channel-coupled receptors, including 5-HT3, GABA, glycine, and nicotinic ACh receptors. Recently, the interaction between local anesthetics and TRPV1 agonist has attracted the attention because they raise the possibilities of producing analgesic effect without affecting motor or other sensory functions. The effects of local anesthetics may have some aspects which have not been clarified. Further investigations will be required to fully understand the actions of local anesthetics.