The combined treatment with anticonvulsant and antidepressant drugs is reported in both neurologic and psychiatric practice; it is, therefore, evident that the issue of managing such type of polytherapy is frequently encountered by clinicians. To review current literature on pharmacokinetic interactions between anticonvulsant and antidepressant drugs. A search of MEDLINE and EMBASE was conducted for original papers and review articles published in English between January 1970 and July 2008. Among antidepressants, older compounds, such as tricyclics and monoaminoxidase inhibitors, have higher potential for interactions than newer ones. In almost all cases, drug dosages need to be adjusted when prescribed in combination with inducers such as carbamazepine, barbiturates and phenytoin. Data concerning new antiepileptic drugs are still limited; however, in several cases, new generation compounds are characterized by a favorable pharmacokinetic profile, thus, limiting the risk of interactions. In fact, gabapentin, topiramate, lamotrigine and levetiracetam are expected to be safely used in association with antidepressants, although it should be considered that topiramate may have interactions at doses higher than 200 mg. Although new generation antidepressants are not equivalent in their potential for interactions, their use seems to be safe in combination with anticonvulsant drugs. When prescribed with well-known inducers, the drug dose needs to be adjusted in relationship with the clinical response.