Powdery mildews (PMs) cause disease in a wide range of plant species including important crops. Taking tomato as an example, here we review findings on the genetic basis and mechanisms of plant resistance to PMs. First, we present a summary of our research on tomato resistance to two PM species, with the focus on Oidium neolycopersici. We discuss the genetics of resistance to this pathogen in tomato. Then, we compare different forms of resistance mediated by different resistance genes based on molecular and cytological data. Also, we provide a comparison between these resistance genes in tomato with those in barley, Arabidopsis and wheat, in order to present a model for the genetic basis of resistance to PMs in plants. We try to accommodate these resistance mechanisms in the current model of plant innate immunity. At the end we discuss possibilities to translate these findings to practical approaches in breeding for resistance to PMs in crops.