Cytomegalovirus (CMV) infection is one of the most important infectious complications of solid-organ transplantation, and is also responsible for serious, life-threatening diseases in patients infected with human immunodeficiency virus (HIV). Tremendous progress has been made with respect to prevention and treatment of CMV disease in such patients. The use of anti-CMV drugs and the immune reconstitution achieved by use of anti-retroviral drugs has reduced the incidence of CMV disease dramatically. Nevertheless, problems of clinical relevance remain (e.g., drug toxicity, drug-drug interactions, antiviral resistance) and new problems have emerged. Intragenic recombination among different CMV strains has been identified as a possible source of novel CMV strains in patients with advanced HIV infection. Development of a protective CMV vaccine remains elusive, perhaps, in part, because of strain-specific variation in immunodominant epitopes. Late-onset CMV disease, which occurs several months or years after transplantation, has been recognised as a clinically relevant complication in transplant recipients. The most effective strategy for the prevention of CMV disease in transplant recipients (i.e., prophylaxis or pre-emptive therapy) remains a matter of debate. A link between CMV infection and Guillain-Barré syndrome, a neurological disease characterised by flaccid paralysis, has been substantiated, but the efficacy of antiviral therapy in such patients remains to be determined. This review summarises the current status of CMV disease in immunocompromised patients, and discusses some of the emerging issues of clinical relevance with regard to CMV infection in patients with disorders of the immune system.