Depressive syndromes represent a disabling comorbidity for many children with autism spectrum disorders (ASD); however, the ascertainment of depression can be complicated by phenotypic overlap between the 2 conditions, by ways in which autistic symptomatology can mask cardinal features of depression and by atypical manifestations of depression in children with ASD. These issues have contributed to wide variation in the estimation of prevalence rates of depression in individuals with ASD and invoke the need for new approaches to the specific detection of depression and other neuropsychiatric comorbidities that aggregate in children affected by ASD. The authors review the scientific literature relevant to the occurrence of depression in ASD and consider important parameters of risk, including psychosocial factors such as insight into affectation status, as well as biological factors such as the aggregation of depressive syndromes in certain families affected by autism, which has suggested possible overlap in genetic influences underlying the 2 conditions. Variability in the manifestations of depression across environmental contexts provides important clues to intervention and underscores the potential importance of involving multiple informants in ascertaining depression in children and adolescents with ASD. A practical strategy for evaluating the presence of depression in youth with ASD is synthesized from the available data and discussed.