The authors sought to summarise and synthesise results from investigations which report on the effect of antidepressants on serum lipid homeostasis. The authors conducted a MedLine search of all English-language articles from 1966 to March 2006 using the search terms: major depressive disorder, bipolar disorder, lipids, triglycerides, cholesterol, low-density lipoprotein, high-density lipoprotein, and the non-proprietary names of conventional antidepressants indicated for the treatment of major depressive disorder in North America as of March 2006. The search was supplemented with a manual review of retrieved articles for any further citations reporting the effects of antidepressants on lipid homeostasis. Despite the paucity of well-characterised investigations, the unfavourable effect of weight gain promoting antidepressants (e.g., tricyclics, mirtazapine) on serum lipid parameters (i.e., triglycerides and low-density lipoprotein cholesterol) is a consistent finding. Weight-neutral antidepressants (e.g., bupropion, venlafaxine, duloxetine), however, are less likely to disrupt the lipid milieu. A weight-independent effect on lipid homeostasis is less consistently reported. Some antidepressants unfavourably influence the lipid milieu; mediating factors other than weight gain are not well-established. Pivotal studies evaluating the therapeutic index of antidepressants need to systematically collect and report data on the lipid effects of antidepressants.