The zebrafish (Danio rerio) has become a very important animal model in biomedical research. In contrast with other models, such as mice, there has been relatively little documentation or control of subclinical disease in zebrafish research facilities. Several infectious and noninfectious conditions are consistently detected by histopathology in apparently healthy D. rerio. The most commonly observed infectious agent in zebrafish is Pseudoloma neurophilia, which is a microsporidian organism that targets the central nervous system, peripheral nerves, and occasionally other tissues. Mycobacteriosis, caused by Mycobacterium chelonae and other species, is also a frequent finding. Less commonly encountered agents include Pseudocapillaria tomentosa, which can cause extensive proliferative enteritis, and a myxozoan (Myxidium sp.) that inhabits the urinary tract but appears to cause few if any pathological changes. Noninfectious diseases that are often clinically unapparent in zebrafish include hepatic megalocytosis, bile and pancreatic ductal proliferation, and neoplasms of the ultimobranchial gland, gastrointestinal tract, and testis. To date, there is little information on the degree to which these conditions may impact research in subclinically affected fish, but there is reason to believe that they should be considered as potentially significant causes of nonprotocol variation in experiments. Therefore, it is imperative that research facilities monitor their stocks for the presence of these occult diseases and be aware of their existence when interpreting study results. Furthermore, for underlying disease conditions that cannot be readily eradicated, it is essential to determine the physiological and immunological changes that they elicit in zebrafish. Understanding the cause, modes of transmission, and distribution of the pathogens would provide useful information for the development of control and prevention strategies.