This chapter explores the pharmacokinetic variability of ketamine, focusing on its metabolism by cytochrome P450 (CYP) enzymes, primarily CYP2B6 and CYP3A4. Ketamine’s widespread use as an anesthetic and analgesic within these metabolic pathways will be discussed, reporting known influencing factors, such as genetic polymorphisms, ethnicity, gender, dietary interactions, and age, each affecting the drug’s clearance and efficacy. Genetic differences, especially the presence of allelic variants like CYP2B6*6, can slow ketamine metabolism and increase plasma concentrations, leading to prolonged effects and a potential increase in adverse reactions. Ethnic and gender differences also contribute to this variability, with certain populations showing slower metabolism. Dietary elements such as grapefruit juice and supplements like St. John’s Wort are highlighted for their potential to inhibit or induce CYP enzymes, thus altering ketamine pharmacokinetics. In view of the wide interindividual variability in metabolism, a one-size-fits-all therapy with ketamine will not be the best possible approach. Our analysis underscores the importance of pharmacogenetic, dietary, and demographic considerations to tailor ketamine therapy to each patient’s unique profile.