Whole-body MRI (WB-MRI) is increasing in clinical acceptance and utilization for a range of indications. WB-MRI is currently an established screening tool for children and adults at high risk of developing malignancy, with the strongest supporting evidence in patients with Li-Fraumeni syndrome. WB-MRI has been added to professional society guidelines for staging disease in patients with certain malignancies including multiple myeloma and has been proposed as a technique to screen for metastatic disease in patients with visceral malignancies including prostate cancer and breast cancer. Emerging data support the utility of WB-MRI in children with malignancies such as Ewing sarcoma, in adults with myxoid liposarcoma, and in pregnant patients with occult or newly detected malignancy. WB-MRI can further help evaluate disease extent and treatment response in patients with nononcologic conditions such as chronic nonbacterial osteomyelitis, myopathy, inflammatory arthritis, and fever of unknown origin. This AJR Expert Panel Narrative Review summarizes available evidence and recommendations supporting the clinical applications of WB-MRI. This article also highlights limitations, barriers, and controversies associated with utilization of WB-MRI in routine clinical practice.