Hydropericardium syndrome (HPS) is a highly infectious disease caused by fowl adenovirus serotype 4 (FAV-4) affecting poultry, especially broiler birds. The disease was initially reported from Angara Goth, Pakistan, and then from India during 1994, in the poultry belt of Jammu and Kashmir, and thereafter, from almost all parts of the country, causing heavy economic losses to the poultry industry. The disease occurs predominantly in broilers of the age group of 3-5 weeks, characterized by sudden onset of high mortality up to 80 %. The causative agent of HPS is fowl adenovirus 4, which is a member of the species Fowl Adenovirus C, genus Aviadenovirus, family Adenoviridae [60]. FAV-4 is non-enveloped and icosahedral in shape, measuring 70-90 nm in size and containing a linear dsDNA of approximately 45 kb in size as its genome. The livers of affected birds show necrotic foci and basophilic intranuclear inclusion bodies in the hepatocytes. The disease can be diagnosed from its gross and microscopic changes in the liver and by various serological tests, such as agar gel immunodiffusion, counterimmunoelectrophoresis, indirect haemagglutination, fluorescent antibody techniques, and ELISA. In the past few years, PCR has been used as a rapid diagnostic tool for the detection of fowl adenoviruses. The disease has been brought under control by the use of formalin-inactivated, attenuated or live vaccines in experimentally infected birds. Advancement in the field of computational immunology accelerates knowledge acquisition and simultaneously reduces the time and effort involved in screening potential epitopes, leading toward the development of epitope-based vaccines.