Abstract: Humans and most animals can have the feeling of pain which is caused by complex mechanisms and has a wide range of influences. Current therapeutics often fail to achieve the desired efficacy and tolerability, leaving the effective treatment of pain remains a challenge. Presently, modulation of ion channel signaling has shown its analgesic advantage. However, among the 215 ion channels in human genome, only 85 of them are strongly associated with pain, and only a few are useful for pain treatment. Here we focused on the latest advances in research of mechanisms of ion channel-targeting analgesic drugs.