The pathophysiology of psychiatric diseases including depression is characterized by the involvement of many genes contributing a small effect. This genetic complexity means larger amounts of information can be gathered by studying the disease process as a single entity, in an animal model. A number of genetically modified animals showing both depressive and anti-depressive phenotypes have been generated. Approximately ten of these models are in current use for screening novel antidepressants. The development of new therapies is intimately linked to the elucidation of mechanisms via which the drugs work and therefore the mechanisms of disease. It is now possible to combine the information from animal models with sophisticated technology including DNA microarray analysis. In this setting, the animal models can provide information about genes altered in both the depressive state and after anti-depressive treatment, whilst DNA microarrays can identify these genes, as well as the direction of change. This information will eventually lead to the discovery of new mechanisms involved in disease pathology. Here we summarize approaches for identifying genes related to depression.