Whole-body magnetic resonance imaging (WB-MRI) is a powerful tool increasingly used to assess oncologic and nononcologic diseases. WB-MRI provides information about diffuse multifocal pathologies with excellent anatomical definition through high soft tissue contrast and spatial resolution as well as valuable functional information from diffusion-weighted images. In addition to its roles in establishing the diagnosis and assessing the extent and severity of disease, WB-MRI is also useful for monitoring the response to treatment for malignant and benign systemic diseases affecting the musculoskeletal system. This article reviews and updates the applications of WB-MRI in current practice, discussing the role of this helpful tool in various conditions involving the musculoskeletal system including bone metastases, hematologic cancers, inflammatory processes, infections, and multisystemic-multifocal bone, nerve, vascular, and muscle/soft tissue disorders, as well as other idiopathic conditions.