The basal ganglia and thalamus are paired deep gray matter structures that may be involved by a wide variety of disease entities. The basal ganglia are highly metabolically active and are symmetrically affected in toxic poisoning, metabolic abnormalities, and neurodegeneration with brain iron accumulation. Both the basal ganglia and thalamus may be affected by other systemic or metabolic disease, degenerative disease, and vascular conditions. Focal flavivirus infections, toxoplasmosis, and primary central nervous system lymphoma may also involve both deep gray matter structures. The thalamus is more typically affected alone by focal conditions than by systemic disease. Radiologists may detect bilateral abnormalities of the basal ganglia and thalamus in different acute and chronic clinical situations, and although magnetic resonance (MR) imaging is the modality of choice for evaluation, the correct diagnosis can be made only by taking all relevant clinical and laboratory information into account. The neuroimaging diagnosis is influenced not only by detection of specific MR imaging features such as restricted diffusion and the presence of hemorrhage, but also by detection of abnormalities involving other parts of the brain, especially the cerebral cortex, brainstem, and white matter. Judicious use of confirmatory neuroimaging investigations, especially diffusion-weighted imaging, MR angiography, MR venography, and MR spectroscopy during the same examination, may help improve characterization of these abnormalities and help narrow the differential diagnosis.