Primary central nervous system lymphoma (PCNSL), once considered a rare brain neoplasm, has been steadily increasing in incidence mainly due to an enlarging population of immunosuppressed patients. PCNSL has become the second most common brain space occupying lesion in patients with the acquired immunodeficiency syndrome. A rapid diagnosis of this entity may represent weeks to months of survival to immunosuppressed HIV-positive patients. The radiologist now plays an important role in the noninvasive diagnosis and management of this condition through the accurate interpretation of imaging findings provided by CT, MR, and brain SPECT studies. This article focuses on the pathogenesis, clinical manifestations, neuropathology, and imaging characteristics of this brain neoplasm. New accurate imaging algorithms combining the diagnostic information provided by CT, MR, and T1-201 brain SPECT are discussed.