Stiff person syndrome (SPS) varies from mild to severe, but if untreated it can be progressive and disabling. Although progress has been made in understanding and treating SPS, the disease remains underdiagnosed, delaying treatment. Antibodies against glutamic acid decarboxylase provide an excellent diagnostic marker, but their role in disease pathogenesis is uncertain. Research focused on identifying new autoantigens has provided evidence that gamma-aminobutyric acid (GABA)(A) receptor-associated protein (GABARAP), a 14-kD protein localized at the postsynaptic regions of GABAergic synapses, is an antigenic target. Circulating anti-GABARAP antibodies that inhibit GABA(A) receptor expression on GABAergic neurons have been found in up to 65% of SPS patients. The impairment of GABAergic pathways and reduction of brain GABA results in clinical manifestations of stiffness, spasms, and phobias. Increased awareness of SPS among practicing physicians is necessary to recognize the disease early and prevent permanent disability. Most patients with SPS respond to GABA-enhancing drugs, but the high doses required cause unacceptable adverse effects. The disease clearly responds to intravenous immunoglobulin, but repeated infusions are needed to maintain response. New immunomodulating agents are being explored to treat difficult cases and to induce long-lasting remissions.