Valproate is an effective anti-epileptic and mood stabilizer drug, but its prescription may be complicated by the development of thrombocytopenia. The purpose of the present manuscript is to provide a critical overview about the risk of thrombocytopenia during treatment with valproate. A search of the main database sources has been conducted to identify relevant papers about the topic. In the studies with a larger sample size (> 150 subjects), thrombocytopenia occurred in 12-18% of subjects receiving treatment with valproate. Advanced age, female gender, and high doses were found to be risk factors for the development of thrombocytopenia during treatment with valproate. Future research is needed to clarify the clinical impact of the occurrence of thrombocytopenia during valproate treatment (e.g., the risk of life-threatening events such as stroke or the development of thrombocytopenia during short- versus long-term administration, or oral versus intravenous formulations).