In the past 2 years, CDC has learned of several clusters of respiratory illness associated with human enterovirus 68 (HEV68), including severe disease. HEV68 is a unique enterovirus that shares epidemiologic and biologic features with human rhinoviruses (HRV). First isolated in California in 1962 from four children with bronchiolitis and pneumonia, HEV68 has been reported rarely since that time and the full spectrum of illness that it can cause is unknown. The six clusters of respiratory illness associated with HEV68 described in this report occurred in Asia, Europe, and the United States during 2008-2010. HEV68 infection was associated with respiratory illness ranging from relatively mild illness that did not require hospitalization to severe illness requiring intensive care and mechanical ventilation. Three cases, two in the Philippines and one in Japan, were fatal. In these six clusters, HEV68 disproportionately occurred among children. CDC learned of clusters of HEV68 from public health agencies requesting consultation or diagnostic assistance and from reports presented at scientific conferences. In each cluster, HEV68 was diagnosed by reverse transcription-polymerase chain reaction (RT-PCR) testing targeting the 5'-nontranslated region, followed by partial sequencing of the structural protein genes, VP4-VP2, VP1, or both, to give definitive, enterovirus type-specific information. This report highlights HEV68 as an increasingly recognized cause of respiratory illness. Clinicians should be aware of HEV68 as one of many causes of viral respiratory disease and should report clusters of unexplained respiratory illness to the appropriate public health agency.