Citrus tristeza virus (CTV) causes two citrus diseases that have caused devastating losses in global citrus production. The first disease is quick decline of trees propagated on the sour orange rootstock. The second disease is stem pitting, which severely affects a number of economically important citrus varieties regardless of the rootstock used and results in reduced tree growth and vigor as well as in reduced fruit size and quality. Both diseases continue to invade new areas. While quick decline could be effectively managed by the use of resistant and/or tolerant rootstocks, the only means to protect commercial citrus against endemic stem pitting isolates of CTV has been cross-protection with mild isolates of the virus. In some citrus areas cross-protection has been successful and allowed production of certain citrus cultivars despite the presence of severe stem pitting isolates in those regions. However, many other attempts to find isolates that would provide sustained protection against aggressive isolates of the virus had failed. In general, there has been no understanding why some mild isolates were effective and others failed to protect. We have been working on the mechanism of cross-protection by CTV. Recent considerable progress has significantly advanced our understanding of how cross-protection may work in the citrus/CTV pathosystem. As we demonstrated, only isolates that belong to the same strain of the virus cross protect against each other, while isolates from different strains do not. We believe that the results of our research could now make finding protecting isolates relatively straightforward. This review discusses some of the history of CTV cross-protection along with the recent findings and our "recipe" for selection of protecting isolates.