Angiosperms are well adapted to tolerate biotic and abiotic stresses in their native environment. However, the growth habit of native plants may not be suited for cultivation and their fruits may not be desirable for consumption. Adapting a plant for cultivation and commercial appeal through breeding and selection may accentuate weaknesses in pest tolerance. The transition of muscadine from a wild, native plant to a cultivated crop has taken place over the last 150 years. Early production primarily involved cloning elite wild selections; few pest management inputs were needed since the material was genetically similar to the native plant. Over time, emphasis was placed on the refinement of pruning, trellising, and other cultural inputs to increase productivity and commercial implementation. In turn, breeders developed newer cultivars with greater productivity and commercial appeal. Many modern muscadine cultivars remain tolerant to biotic pests and are adapted to a hot and humid climate. The primary focus of this review is to provide a descriptive context of muscadine as a native American, perennial fruit crop that requires minimal pest management in hot, humid climates relative to recently introduced European bunch grapes. Inherent muscadine traits resulting in fewer pesticide inputs make them worthy of being planted across considerable acreages; yet, muscadines remain a niche crop. We conclude that muscadines suffer from their short history of cultivation in a confined region and would benefit from breeding and marketing efforts to increase consumption, commercial acceptance, and awareness.