Introduction: Statins have been widely used in clinical practice; however, the association between statin use and depression is complex as research findings have been mixed. We know that cholesterol plays an important role in the serotonin system, so statins used to lower cholesterol may lead to the occurrence of depression. Areas covered: This article reviews i) cholesterol function in the brain, ii) how low cholesterol can cause depression, iii) a brief introduction of the serotonin system and how low cholesterol can disturb it, iv) neurosteroids and how they may lead to depression, and v) some direct evidence that statins can cause depression as well as contradicting evidence. Preparation of this article included an extensive literature search of statins and depression using PubMed from 1972 to 2012. Expert opinion: This article shows that statins could lead to depression by lowering cholesterol and that we should draw attention to this in clinical application, especially for patients complicated with depressive symptoms or low serum cholesterol levels.