Psychiatric classifications categorize how patients present to mental health care professionals and are necessarily utilitarian. From the clinician’s perspective, the most important goal of a psychiatric classification is to assist them in managing their patients’ psychiatric conditions by facilitating the selection of effective interventions and predicting management needs and outcomes. Due to the field’s lack of understanding of the neurobiological mechanisms underlying the psychiatric disorders in both the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD), diagnosis and treatment are only loosely related, thus limiting clinical utility. Both DSM and the chapter on mental and behavioral disorders in ICD adopted a descriptive atheoretical categorical approach that defines mental disorders according to syndromal patterns of presenting symptoms. This chapter discusses the fundamental challenges that underlie this decision. It then reviews the Research Domain Criteria (RDoC) project, a research framework established by the U.S. National Institute of Mental Health (NIMH) to assist researchers in relating the fundamental domains of behavioral functioning to their underlying neurobiological components. Designed to support the acquisition of knowledge of causal mechanisms underlying mental disorders, RDoC may facilitate a future paradigm shift in the classification of mental disorder.