Cross-protection is a phenomenon in which infection of a plant with a mild virus or viroid strain protects it from disease resulting from a subsequent encounter with a severe strain of the same virus or viroid. In this chapter, we review the history of cross-protection with regard to the development of ideas concerning its likely mechanisms, including RNA silencing and exclusion, and its influence on the early development of genetically engineered virus resistance. We also examine examples of the practical use of cross-protection in averting crop losses due to viruses, as well as the use of satellite RNAs to ameliorate the impact of virus-induced diseases. We also discuss the potential of cross-protection to contribute in future to the maintenance of crop health in the face of emerging virus diseases and related threats to agricultural production.