The NPR1 (NONEXPRESSOR OF PATHOGENESIS RELATED GENES1) gene has a central role in the long-lasting, broad-spectrum defense response known as systemic acquired resistance (SAR). When overexpressed in a transgenic context in Arabidopsis thaliana, this gene enhances resistance to a number of biotic and abiotic stresses. Its position as a key regulator of defense across diverse plant species makes NPR1 a strong candidate gene for genetic engineering disease and stress tolerance into other crops. High-value horticultural crops face many new challenges from pests and pathogens, and their emergence exceeds the pace of traditional breeding, making the application of NPR1-based strategies potentially useful in fruit and vegetable crops. However, plants overexpressing NPR1 occasionally present detrimental morphological traits that make its application less attractive. The practical utility of NPR-based approaches will be a balance of resistance gains versus other losses. In this review, we summarize the progress on the understanding of NPR1-centered applications in horticultural and other crop plants. We also discuss the effect of the ectopic expression of the A. thaliana NPR1 gene and its orthologs in crop plants and outline the future challenges of using NPR1 in agricultural applications.