This paper analyses the potential gains and the main challenges for increased cross-border collaboration in the control of highly contagious livestock diseases in regions with cross-border reliance on production and consumption of livestock commodities. The aim of this intensification of cross-border collaboration is to retain the economic advantages of cross-border trade in livestock and livestock commodities while maintaining a low risk of highly contagious livestock diseases. From these two foci, possibilities for future policy making with respect to highly contagious livestock diseases are discussed: peacetime cross-border cooperation to improve the cost-effectiveness of routine veterinary measures and crisis time cross-border harmonization of current disease control strategies. A general disease management framework was used to describe the way in which these two fields are related to and affect the epidemiological system and, consequently, how they impact the stakeholders. In addition to this framework, the importance of a good understanding of influencing factors, that is, the production structure of livestock, was stressed because these factors are important determinants of the frequency and magnitude of highly contagious livestock diseases and their economic impact. The use of the suggested integrated approach was illustrated for the extended cross-border region of the Netherlands and Germany, that is, North Rhine Westphalia and Lower Saxony. For this region, current difficulties in cross-border trade in livestock and livestock commodities and possibilities for future cross-border collaboration were examined. The concepts and ideas presented in this paper should foster future development of cross-border collaboration in animal health control.