Abstract: An important economic crop and model plant, Nicotiana tabacum and its yield and quality carry a significant weight on the national agriculture and affect tobacco farmers’ income directly. Among the AP2/ERF transcription factors that play important roles in the development, hormone signaling, and stress responses of plants, the ERF subfamily, which was characterized by its unique AP2 domain and diverse functional motifs, has unsurprisingly become a focal point in studying tobacco growth and metabolic regulation. This article summarizes the structure and classification of the ERF transcription factors and their regulatory functions in seed germination, organ formation, photosynthesis, and nicotine biosynthesis. The mechanisms by which ERFs mediate the responses of a tobacco plant to abiotic stresses (e.g., drought, low temperature, and salinity) as well as biotic stresses (e.g., pathogen infection) and the enhanced stress adaptation of the plant through the activation of resistance-related genes and/or modulation of associated hormone signaling pathways by the ERFs are highlighted. Areas continue to be explored, such as functional characterization of individual ERFs, regulatory networks, and protein interactions, are discussed. Applications of multi-omics, gene editing, and protein interaction technologies for identifying specific functions and elucidating roles in the network are also proposed. It was aimed at advancing molecular breeding to generate tobacco varieties, and possibly other crops, with enhanced stress tolerance and desirable quality via targeted ERF gene manipulation.