Plant virus management strategies have largely been limited to the application of hygiene protocols, the control of viral vectors such as insects and nematodes and the use of resistant varieties. However, these approaches are often insufficient to prevent infections. The rapid control of newly emerging viral diseases remains challenging. This chapter focuses on cross-protection using mild viruses as active substances in biocontrol. The chapter begins by describing the theoretical modes of action of cross-protection. It then goes on to discuss crucial elements in the development of a cross-protection strategy, taking into account new insights based on commercial application of cross-protection. The chapter also provides case studies in which cross-protection has been applied in commercial crops, in particular vaccination strategies to control Pepino mosaic virus (PepMV) in greenhouse tomato. Finally, developments that may impact future research into the control of emerging viral pathogens are discussed.