In patients with HIV, Toxoplasma gondii is the most frequent infectious cause of focal brain lesions. Particularly in advanced HIV disease, it can cause significant morbidity and mortality. Current clinical practice involves empiric therapy with pyrimethamine and sulfadiazine, upon a presumptive diagnosis of toxoplasmic encephalitis, based on serologic, clinical, and radiological features. This approach continues to evolve, as new diagnostic strategies, such as the use of immunoglobulin G antibody titers and polymerase chain reaction, prophylaxis against opportunistic infections, and highly active antiretroviral therapy--HAART--come into play. Primary and secondary prophylaxis are the mainstay of treatment. There remains a continuing need for development of new anti-Toxoplasma therapy.