Disorders of gut-brain interaction, previously known as functional gastrointestinal disorders (eg, functional dyspepsia and irritable bowel syndrome), are commonly encountered in both the primary care and gastroenterology clinics. These disorders are often associated with high morbidity and poor patient quality of life and often lead to increased health care use. The management of these disorders can be challenging, as patients often present after having undergone an extensive workup without a definite etiology. In this review, we provide a practical five-step approach to the clinical assessment and management of disorders of gut-brain interaction. The five-step approach includes (1) excluding organic etiologies of the patient's symptoms and using Rome IV criteria for diagnosis, (2) empathizing with the patient to develop trust and a therapeutic relationship, (3) educating the patient about the pathophysiology of these gastrointestinal disorders, (4) expectation setting with a focus on improving function and quality of life, and (5) establishing a treatment plan with central and peripherally acting medications and nonpharmacological modalities. We discuss the pathophysiology of disorders of gut-brain interaction (eg, visceral hypersensitivity), initial assessment and risk stratification, as well as treatment for a variety of diseases with a focus on irritable bowel syndrome and functional dyspepsia.