Background: Depression has been frequently reported in individuals with Down Syndrome (DS). The aim of this article is to provide a comprehensive, critical review of the clinically relevant literature concerning depression in DS, with a focus on epidemiology, potential risk factors, diagnosis, course characteristics and treatment. Methods: We searched the PUBMED database (January 2011) using the keywords ("Depressive Disorder [MESH]" OR "Depression [MESH]" OR "depress* [All Fields]") AND ("Down Syndrome [MESH]" OR "Down syndrome [All Fields]" OR "Down's syndrome [All Fields]"). Review articles not adding new information, single case reports and papers focusing on subjects other than depression in DS were excluded. Results: The PUBMED search resulted in 390 articles, of which 30 articles were finally included. Recent information does not support earlier suggestions of an increased prevalence of depression in DS compared to other causes of Intellectual Disability (ID). However, individuals with DS show many vulnerabilities and are exposed to high levels of stressors that could confer an increased risk for the development of depression. Apart from general risk factors, several potential risk factors are more specific for DS, including smaller hippocampal volumes, certain changes in neurotransmitter systems, deficits in language and working memory, attachment behaviours and frequently occurring somatic disorders. Protective factors might play a role in reducing the vulnerability to depression. The diagnosis of depression in DS is mainly based upon observable characteristics, and therefore, the use of modified diagnostic criteria is advised. Although several common treatments, including antidepressants, electroconvulsive therapy and psychotherapy seem effective, there is evidence of undertreatment of depression in DS. Conclusions: There are important limitations to our current clinical knowledge of depression in DS. Future studies should include systematic evaluations of pharmacotherapeutic and psychotherapeutic interventions.