Local anesthetic systemic toxicity (LAST) is a life-threatening adverse event that may occur after the administration of local anesthetic drugs through a variety of routes. Increasing use of local anesthetic techniques in various healthcare settings makes contemporary understanding of LAST highly relevant. Recent data have demonstrated that the underlying mechanisms of LAST are multifactorial, with diverse cellular effects in the central nervous system and cardiovascular system. Although neurological presentation is most common, LAST often presents atypically, and one-fifth of the reported cases present with isolated cardiovascular disturbance. There are several risk factors that are associated with the drug used and the administration technique. LAST can be mitigated by targeting the modifiable risk factors, including the use of ultrasound for regional anesthetic techniques and restricting drug dosage. There have been significant developments in our understanding of LAST treatment. Key advances include early administration of lipid emulsion therapy, prompt seizure management, and careful selection of cardiovascular supportive pharmacotherapy. Cognizance of the mechanisms, risk factors, prevention, and therapy of LAST is vital to any practitioner using local anesthetic drugs in their clinical practice.