Therapeutic drug monitoring (TDM) in pediatrics (0-14 years) is especially important because the absorption, distribution, metabolism, and excretion of drugs and drug pharmacokinetic profiles can be different from that of the adult population. In this context, several parameters like half-life of drug elimination from the body (t½), peak plasma concentration (Cmax), area under the curve, clearance (CL), Tmax, and dose/concentration relationship in children may differ from adults. Hence, the knowledge of pharmacokinetic parameters and therapeutic and toxic ranges of drug concentrations may help the clinicians to optimize drug treatment regimens in the pediatric population. TDM of psychotropic drugs requires particular attention for the pharmacological and clinical consequences of nonadequate dose use, lack in the compliance, and overdoses with possible toxic effects. Psychoactive drugs such as benzodiazepines, antiepileptic drugs, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotic drugs, psychostimulants (attention-deficit hyperactivity disorder drugs), opioid analgesics, and antimigraine drugs are a heterogeneous group. These drugs are subject to interindividual variability, and therefore, the usefulness of TDM for these drugs has to be assessed individually. Because of the occurrence of comorbid pathologies, including psychiatric disorders, the use of combined pharmacotherapy is not uncommon. As a consequence, these patients may be at risk from a number of potential drug-drug interactions. The implementation of TDM in pediatric population is more difficult than in adults because some sampling procedures are invasive and cause discomfort in children, and additionally, they require the cooperation of the patient. Several examples will be provided where the use of alternative matrices, such as saliva, is proposed to minimize inconvenience and patient discomfort.