Abstract: The expansion of fruit production and markets into new geographic areas provides novel opportunities and challenges for the agricultural and marketing industries. Evidence that fruit consumption helps prevent nutrient deficiencies and reduces the risk of cardiovascular disease and cancer has assisted in the expansion of all aspects of the fruit industry. In today’s competitive global market environment, producers need access to the best plant material available in terms of genetics and health if they are to maintain a competitive advantage in the market. An ever-increasing amount of plant material in the form of produce, nursery plants, and breeding stock moves vast distances, and this has resulted in an increased risk of pest and disease introductions into new areas. One of the primary concerns of the global fruit industry is a group of systemic pathogens for which there are no effective remedies once plants are infected. These pathogens and diseases require expensive management and control procedures at nurseries and by producers locally and nationally. Here, we review (i) the characteristics of some of these pathogens, (ii) the history and economic consequences of some notable disease epidemics caused by these pathogens, (iii) the changes in agricultural trade that have exacerbated the risk of pathogen introduction, (iv) the path to production of healthy plants through the U.S. National Clean Plant Network and state certification programs, (v) the economic value of clean stock to nurseries and fruit growers in the United States, and (vi) current efforts to develop and harmonize effective nursery certification programs within the United States as well as with global trading partners.