The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers a complex pharmacological profile which has led to its established role in anesthesia, analgesia, and psychiatry. Pharmacokinetic (PK) and pharmacodynamic (PD) models have characterized ketamine’s unique pharmacokinetics which are affected by many factors, such as route of administration, bioavailability, and patient characteristics. Ketamine’s rapid onset and offset of effects can be described with two- or three-compartment models without taking metabolites into account. Ketamine racemate is an equimolar mixture of dextrorotatory S(+)- and levorotatory R(−)-ketamine. PK/PD models have helped to explain the differences between the racemate and its stereoisomers, confirming the approximately two times greater clinical potency of esketamine versus racemate in analgesic and anesthetic, and likely antidepressant action. Recent PK/PD data highlight new insights for patient management, including better-informed approaches to opioid-related respiratory depression and chronic pain. PK/PD models can feature the complex relationships between ketamine administration, clinical response, and safety issues, improving ketamine use schedules while reducing unwanted effects.