Cannabis sativa L. (cannabis) indoor cultivation is severely threatened by the ascomycete pathogen Golovinomyces cichoracearum, the causal agent of the powdery mildew (PM) disease. PM can be controlled by different means including the application of approved IPM products, altering cultural conditions and more importantly, breeding for genetic resistance. Conventional breeding activities in the legacy market during the past decades have been mainly focused on higher potency and yield. This trend, coupled with the liberal use of pesticides to control pest and pathogens, has resulted in the loss of disease resistance (R) genes in the genetic pool of the available cannabis cultivars. Landraces and exotic genotypes of cannabis, on the other hand, offer a great source of resistance alleles, particularly for economically important pathogenic fungi like PM. Here we present our latest findings on the interaction of different agronomic traits and PM disease resistance in a diversity panel comprising of more than a hundred of cannabis landraces and exotic genotypes. Our results indicate that genetic resistance to PM is independent of major agronomic traits. Moreover, novel effective resistance mechanisms against PM were identified and studied at the cellular level.