Carbamazepine (CBZ) is a widely used medication in treating epilepsy, bipolar disorder, and neuropathic pain. Its pharmacokinetic profile is highly variable due to slow absorption, extensive metabolism, and auto-induction. Genetic polymorphisms affect transporters and metabolic enzymes, additionally modifying therapeutic response, and lead to nonlinear and unpredictable toxicokinetics in overdose. CBZ is primarily metabolized by cytochrome P450 (CYP) enzymes CYP3A4, CYP3A5, and CYP2C8 to the active metabolite CBZ-10, 11-epoxide (CBZ-E), with subsequent hydrolysis by epoxide hydrolase 1 (EPHX1) and glucuronidation by uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7), with other CYPs additionally contributing to the formation of reactive intermediates and inactive CBZ metabolites. Polymorphisms in genes encoding enzymes (EPHX1, CYP3A4/5, and UGT2B7) and transporters (ABCB1, ABCC2, RALBP1) can affect CBZ and CBZ-E exposure, maintenance dose, and the risk of adverse drug reactions. In overdose cases, CBZ exhibits saturable epoxidation, which leads to the accumulation of the drug and its active metabolite, prolonged elimination, and neurotoxicity, while serum concentrations correlate poorly with clinical findings. Therapeutic monitoring of the drug and its active metabolite in patients’ blood, together with pharmacogenetic testing, could improve both the individualization of therapy and the management of overdose.