The spine is frequently involved in systemic diseases, including those with neuropathic, infectious, inflammatory, rheumatologic, metabolic, and neoplastic etiologies. This article provides an overview of systemic disorders that may affect the spine, which can be subdivided into disorders predominantly involving the musculoskeletal system (including bones, joints, disks, muscles, and tendons) versus those predominantly involving the nervous system. By identifying the predominant pattern of spine involvement, a succinct, appropriate differential diagnosis can be generated. The importance of reviewing the medical record, as well as prior medical imaging (including nonspine imaging), which may confer greater specificity to the differential diagnosis, is stressed.