Stiff-person syndrome, also known as stiff-man syndrome (SMS) or the Moersch–Woltman syndrome, was first described in 1956. The disease is rare. The estimated prevalence in the general population is 1–2 cases/1,000,000, and the annual incidence is 1 case per 1,000,000. It is 2–3 times more common in females. Symptoms usually occur in 20–50-year-olds; childhood-onset stiff-man syndrome accounts for 5% of cases. Based on the pathogenesis of the disorder, paraneoplastic, autoimmune and cryptogenic stiff-person syndrome have been described, whereas clinicians distinguish between classical stiff-person syndrome and its variants. Diagnostic criteria for the syndrome have been developed and it was shown that overlapping autoimmune diseases increase the risk of the disorder. There are two main clinical presentations of the disorder: 1) muscle stiffness in the trunk and limbs due to simultaneous contraction of agonist and antagonist muscles, and 2) the above clinical picture concomitant with superimposed episodic muscle spasms in the absence of pyramidal and extrapyramidal disorders. Although stiff-person syndrome is associated with antibodies against glutamic acid decarboxylase and amphiphysin, their presence is not necessary for the diagnosis. Patients with paraneoplastic syndrome, which accounts for 5–10% of cases, should be always screened for cancer. The treatment should be multidirectional and include: 1) immunomodulation, 2) symptomatic treatment, 3) monitoring, diagnosis and treatment of overlapping autoimmune and/or neoplastic diseases.