Local anesthetics are still incompletely understood, and none of the currently available drugs are optimal. The primary target of local anesthetics is the voltage-gated sodium channel (VGSC), where they lead to a temporary interruption of nerve conduction. Unfortunately, local anesthetics are neither specific at blocking a specific VGSC isoform, nor a specific cell type. We realize now that the old classification of A and C fibers according to myelin thickness is outdated, that next to differing myelin configuration, cells differ also by their molecular biology, and that there are close to 20 different neuronal subgroups when function is concerned. The ideal local anesthetic would only block sensory impulses, or even only painful impulses. In the search for that drug, several research avenues have been followed. First, efforts have been undertaken to extend duration of local anesthetics, by additives or extended-release formulation. Second, blockade of specific pain fibers has been attempted by targeting permanently charged anesthetics specifically into nociceptors. Third, blockade of specific isoforms using antibodies, and adaptation of naturally occurring neurotoxins has shown promise. Lastly, combination of local anesthetics with other analgesics may improve their duration of action.