Powdery mildew (PM) is one of the most common Cannabis sativa diseases. In spite of this, very few documented studies have characterized the resistance genes involved in PM defense mechanisms, or sources of natural genetic resistance in cannabis. The focus of the present work is on the two primary mechanisms for qualitative resistance against PM. The first is based on resistance (R) genes characterized by conserved nucleotide-binding site and/or leucine-rich repeat domains (NLRs). The second one involves susceptibility (S) genes, and particularly mildew resistance locus o (MLO) genes, whose loss-of-function mutations seem to be a reliable way to protect plants from PM infection. Cannabis defenses against PM are thus discussed, mainly detailing the strategies based on these two mechanisms. Emerging studies about this research topic are also reported and, based on the most significant results, a potential PM resistance model in cannabis plant–pathogen interactions is proposed. Finally, innovative approaches, based on the pyramiding of multiple R genes, as well as on genetic engineering and genome editing methods knocking out S genes, are discussed, to obtain durable PM-resistant cannabis cultivars with a broad-spectrum resistance range. © 2023 by the author.

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