Coffee is one of the most consumed beverages in the world. It is also one of the most globally traded commodities. Coffee leaf rust (CLR), caused by the biotrophic fungus Hemileia vastatrix, is the most important disease affecting Arabica coffee growing worldwide, leading to significant yield losses if no control measures are applied. A deep understanding of the complex mechanisms involved in coffee-H. vastatrix interactions, such as the pathogen variability and the mechanisms governing plant resistance and susceptibility, is required to breed efficiently for durable resistance and design new approaches for crop protection. Here we summarize our current understanding across multiple areas related to pathogen infection, variability and candidate effectors, breeding for disease resistance, and the various components of the coffee immune system, by reviewing a comprehensive body of research on CLR and the advances recently made. We also update information about the defense responses activated by the application of plant resistance inducers, a promising alternative to fungicides in the control of CLR. Moreover, we identify and discuss future directions for further research.