Zoonoses, diseases transmitted between animals and humans, have been a concern in laboratory animal medicine for decades. Exposure to zoonotic organisms not only poses health risks to personnel and research animals but may also affect research integrity. Early laboratory animal programs were ineffective at excluding and preventing transmission of zoonotic diseases: the health status of the animals were often unknown, endemic diseases occurred frequently, housing conditions were less controlled, and veterinary care programs were decentralized. Over time, these conditions improved, but despite this, zoonotic diseases remain a contemporary concern. To reduce the incidence of zoonoses, management should perform an accurate risk assessment that takes into account the type of research performed, animal species used, animal sources, and housing conditions. Specific research practices, such as the use of biological materials, can also affect the risk assessment and should be considered. Once identified, the characteristics of significant zoonotic organisms can be examined. In addition, personnel attitudes and training, facility design and management, equipment availability, personal protective equipment used, standard operating procedures, and the institution's vermin control program can impact the risk assessment. The effectiveness of the occupational health and safety program at managing risks of zoonoses should also be examined. Risk assessment, in the context of zoonotic disease prevention, is a complex exercise and is most effective when a team approach is used and includes research, husbandry, veterinary, and biosafety personnel.