The Unexplained Respiratory Disease Outbreak (URDO) working group is a multidisciplinary team composed of approximately 40 scientists from across CDC with expertise in infectious and noninfectious respiratory diseases. The URDO working group was formed in 2004 to streamline CDC response efforts to assist local, state, and international public health officials in investigations of unexplained respiratory disease outbreaks. This report summarizes URDO working group activities from March 2007 through September 2011. During that period, the URDO working group was notified of 57 investigations and facilitated consultations with subject matter experts (in all 57 investigations), laboratory testing at CDC (in 42 investigations), and on-site field investigation support (in eight investigations). Of these 57 investigations, 41 occurred domestically, and 16 occurred internationally. An etiology was identified in 29 (51%) investigations; among these, the most commonly implicated pathogens were noninfluenza respiratory viruses (41%), influenza viruses (17%), Mycoplasma pneumoniae (14%), and Bordetella pertussis (14%). Notification occurred a median of 33 days after illness onset in the first case, which might have limited the ability to collect early laboratory specimens or epidemiologic data. Reducing delays in sample collection, epidemiologic investigations, and consultation with the URDO working group might increase the ability to identify etiologies and lead to more rapid control of these unexplained respiratory disease outbreaks.