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This review seeks to address 10 essential questions regarding the clinical use of local anaesthetics. Each local anaesthetic has distinctive physicochemical properties but with the same mode of action; they block voltage-gated sodium channels in the axon. Sodium channel block is brought about by a conformational change and the creation of a positive charge in the channel pore. Different local anaesthetics can reach the local anaesthetic binding site in the axon from the cytoplasmic compartment (classic hydrophilic pathway), or directly via its lipid membrane (hydrophobic pathway), or can enter via large-pore channels (alternative hydrophilic pathway). Beyond the nervous system, local anaesthetics exert beneficial effects on pain and can affect the inflammatory response and the haemostatic system. There are problems with the efficacy of local anaesthetics in the presence of local inflammation, and with significant intravascular toxicity, which can be fatal. But when preventive measures are taken, the incidence of cardiac arrest is low. Intralipid has been proposed to treat systemic local anaesthetic overdose and has been enthusiastically adopted worldwide, even though the mechanism of action is incompletely understood. Intralipid is an aid to the management of local anaesthetic toxicity rather than an antidote and meticulous conduct of regional anaesthesia remains paramount. All local anaesthetics are toxic, in a dose- and time-dependent manner, on virtually all tissues, including nerves and muscles. The question of whether local anaesthetics protect against perioperative tumour progression cannot be answered at this moment, and results from clinical (retrospective) studies are equivocal. Future areas of interest will be the design of new subtype-specific sodium channel blockers, but as we look forward, older local anaesthetics such as 2-chloroprocaine are being reintroduced into the clinical setting. Multimodal perineural analgesia and liposomal bupivacaine may replace catheter techniques for some indications.