Esketamine was approved for adults with treatment-resistant depression (TRD) in conjunction with an oral antidepressant, and for treating depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. However, evidence of great efficacy and safety of esketamine is accompanied by a widespread concern regarding its addictive potential.A comprehensive review on the craving and addictive potential of ketamine and esketamine was carried out. In addition, a clinical case of a 34-year-old TRD woman treated with esketamine who experienced drug-seeking behaviors and craving symptomatology was described and critically discussed, with a particular focus on treatment strategies to manage craving in the short- and long term.Esketamine showed great efficacy and safety in treating TRD and MDD with acute suicidal ideation or behavior. Our clinical experience demonstrated the presence of an additive potential, which has been favorably managed with slow esketamine de-titration and combination with bupropion. However, literature so far published is scant and shows contradictory findings. Therefore, it is crucial to promptly detect and manage craving symptomatology in esketamine-treated TRD patients. In our experience, the use of bupropion to counteract craving and addictive symptoms was proven to be effective and safe.