Adenoviruses (Ads) are common opportunistic pathogens that are rarely associated with severe clinical symptoms in healthy individuals. In contrast, in patients with compromised immunity, Ad infections often result in disseminated and potentially life-threatening disease. Among these are AIDS patients, individuals with hereditary immunodeficiencies and recipients of solid organ or haematopoietic stem cell transplants (HSCT) who receive immunosuppressive therapy. The latter account for the largest number of severe Ad infections. There is currently no formally approved antiviral therapy for the treatment of severe Ad keratoconjunctivitis and life-threatening Ad infections in immunocompromised patients. Here we update current knowledge on Ad biology, the clinical features observed in different patient groups and specific immune responses towards Ad infections. In addition, we review current and future treatment options, including: (i) the antiviral drugs cidofovir, ribavirin and new investigational compounds, as evaluated in the clinic or in relevant animal models, as well as (ii) novel immunotherapeutic strategies.