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Mutant phenotypes often vary across genetically distinct individuals. To identify the causes of such genetic background effects, we studied differences in gene essentiality across 18 genetically diverse natural yeast strains. We identified 39 genes that were essential in the laboratory reference strain but not in at least one other genetic background, and we mapped and validated the genetic variants that were responsible for the differences in gene essentiality. These variants typically occurred in single modifier genes that tended to differ between genetic backgrounds. The affected genes often indirectly compensated for the loss of the essential gene and identified naturally occurring evolutionary trajectories. Overall, our results highlight the prevalence of changes in gene essentiality in natural populations, as well as the underlying mechanisms. A thorough understanding of the causes of genetic background effects is crucial for the interpretation of genotype-to-phenotype relationships, including those associated with human disease.