Comorbidity in clinical youth populations is more the rule than the exception, yet few established guidelines exist to help practicing clinicians manage complex diagnostic profiles. The current paper reviews efforts within the treatment development literature to handle comorbidity in depressed and anxious children and adolescents, including single-target, modular-based, and transdiagnostic interventions. Two case studies are presented to describe how comorbid anxiety and depression are managed within two different evidence-based single-target interventions. A third case is presented to introduce a novel individual behavioral activation therapy (IBAT) designed to address co-occurring depression and anxiety by targeting a single maintaining mechanism (avoidance) that underlies both disorders. Implications for clinical decision-making (assessing complex clinical profiles in practice, prioritizing treatment goals, selecting interventions from a broad evidence base) are discussed. (Contains 1 table.)