Although hopelessness has been linked to depression for centuries, the diagnostic criteria for depression are inconsistent with regard to the status of hopelessness. Most research on hopelessness and depression has focused on adults. The current study examined this relation in children and adolescents. Integrative data analyses with a pooled sample (N = 2466) showed that clinical levels of hopelessness multiplied the odds of having a clinical diagnosis of depression 10-fold. Conversely, not having clinical levels of hopelessness multiplied the odds of endorsing no clinical level of depressive symptoms 28-fold. Moreover, results differed by levels of depression: (a) among youths with clinical levels of depression, hopelessness was associated with six depressive symptoms; (b) among youths without clinical levels of depression, hopelessness was associated with nine depressive symptoms. We found that hopelessness helps to explain the heterogeneity of depressive presentations. Our finding supports the consideration of hopelessness in the diagnosis (if not treatment and prevention) of depression in children and adolescents. (PsycInfo Database Record (c) 2021 APA, all rights reserved).