Mental health problems in early childhood are common, but there is a lack of psychiatric research on this age group. DC:0-5 is a multiaxial classification system for mental disorders in early childhood, providing a framework for standardizing clinical practice and research. However, research on the validity of DC:0-5 is scarce. The Developmental Psychiatry Diagnostic Challenges Study (DePsy) is a multi-site, prospective clinical study including six German early childhood mental health (ECMH) clinics. The main objective of the study is to contribute to the validation of Axis I and Axis II of DC:0-5. A second aim of the study is to describe the population of the participating clinics regarding diagnoses, family context, and treatment outcomes. Additionally, the impact of environmental risk factors, including parental Adverse Childhood Experiences (ACEs) and media use, on child psychopathology and caregiver–child relationships will be examined. Over two years, patients aged 0.0–5.9 years old will be enrolled in the study. Assessments include ICD-10 and DC:0-5 diagnoses, developmental tests, video-based observations of caregiver—child interactions, and questionnaires on child psychopathology, media use, parental stress, and treatment satisfaction. Study results will promote the standardization of assessment and treatment in ECMH clinics aiming to improve the development of patients and their families.