Fleshy fruits become more susceptible to pathogen infection when they ripen; for example, changes in cell wall properties related to softening make it easier for pathogens to infect fruits. The need for high‐quality fruit has driven extensive research on improving pathogen resistance in important fruit crops such as tomato (Solanum lycopersicum). In this review, we summarize current progress in understanding how changes in fruit properties during ripening affect infection by pathogens. These changes affect physical barriers that limit pathogen entry, such as the fruit epidermis and its cuticle, along with other defenses that limit pathogen growth, such as preformed and induced defense compounds. The plant immune system also protects ripening fruit by recognizing pathogens and initiating defense responses involving reactive oxygen species production, mitogen‐activated protein kinase signaling cascades, and jasmonic acid, salicylic acid, ethylene, and abscisic acid signaling. These phytohormones regulate an intricate web of transcription factors (TFs) that activate resistance mechanisms, including the expression of pathogenesis‐related genes. In tomato, ripening regulators, such as RIPENING INHIBITOR and NON_RIPENING, not only regulate ripening but also influence fruit defenses against pathogens. Moreover, members of the ETHYLENE RESPONSE FACTOR (ERF) family play pivotal and distinct roles in ripening and defense, with different members being regulated by different phytohormones. We also discuss the interaction of ripening‐related and defense‐related TFs with the Mediator transcription complex. As the ripening processes in climacteric and non‐climacteric fruits share many similarities, these processes have broad applications across fruiting crops. Further research on the individual contributions of ERFs and other TFs will inform efforts to diminish disease susceptibility in ripe fruit, satisfy the growing demand for high‐quality fruit and decrease food waste and related economic losses.
