SummaryThe capacity of plants to counter the challenge of pathogenic fungal attack depends in part on the ability of plant defense proteins to overcome fungal resistance by being able to recognize and eradicate the invading fungi. Fungal genes that control resistance to plant defense proteins are therefore important determinants that define the range of fungi from which an induced defense protein can protect the plant. Resistance of the model fungus Saccharomyces cerevisiae to osmotin, a plant defense PR‐5 protein, is strongly dependent on the natural polymorphism of the SSD1 gene. Expression of the SSD1‐v allele afforded resistance to the antifungal protein. Conversely, yeast strains carrying the SSD1‐d allele or a null ssd1Δ mutation displayed high sensitivity to osmotin. The SSD1‐v protein mediates osmotin resistance in a cell wall‐dependent manner. Deletion of SSD1‐v or SSD1‐d impeded sorting of the PIR proteins (osmotin‐resistance factors) to the cell wall without affecting mRNA levels, indicating that SSD1 functions in post‐transcriptional regulation of gene expression. The sensitivity of ssd1Δ cells to osmotin was only partially suppressed by over‐accumulation of PIR proteins in the cell wall, suggesting an additional function for SSD1 in cell wall‐mediated resistance. Accordingly, cells carrying a null ssd1 mutation also displayed aberrant cell‐wall morphology and lower levels of alkali‐insoluble cell‐wall glucans. Therefore SSD1 is an important regulator of fungal cell‐wall biogenesis and composition, including the deposition of PIR proteins which block the action of plant antifungal PR‐5 proteins.