The potential clinical usefulness of therapeutic drug monitoring (TDM) in neonates is discussed. The personnel performing neonatal TDM must be knowledgeable in the many clinical, analytical, and pharmacokinetic variables used for measuring drug concentrations to formulate rational, individualized dosing regimens. Examples of variables and their effects on TDM interpretations are given and some gaps in our knowledge are presented. The theoretical promise of neonatal TDM is contrasted with the practical realities.