Multiple myeloma is a heterogeneous group of plasma cell neoplasms that primarily involve bone marrow but also may occur in the soft tissue. Although the disease varies in its manifestations and its course, it is eventually fatal in all cases. Over the past 2 decades, significant advances have been made in our understanding of the genetics and pathogenesis of multiple myeloma and in its treatment. The use of magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) has improved sensitivity for the detection of this disease. PET aids in the identification of active multiple myeloma on the basis of FDG uptake, and MR imaging helps identify multiple myeloma from its infiltration of normal fat within the bone marrow, which occurs in characteristic patterns that correlate with the disease stage. The increased sensitivity of these advanced cross-sectional imaging techniques has led to further refinement of the classic Durie and Salmon staging system. In addition, these imaging techniques allow a more reliable assessment of the disease response to treatment with current regimens, which may include autologous stem cell transplantation as well as various medications. In lesions that respond to chemotherapeutic agents, the replacement of previously infiltrated marrow by fat is seen at MR imaging and decreased FDG uptake is seen at FDG PET; however, a lengthy and intensive regimen may be necessary before the MR imaging appearance of marrow normalizes. Lytic lesions seen at CT almost always persist even after successful treatment. To provide an accurate assessment, radiologists must be familiar not only with the appearances of multiple myeloma and its mimics but also with common treatment-related findings.