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While switch-like gene expression (“on” in some individuals and “off” in others) has been linked to biological variation and disease susceptibility, a systematic analysis across tissues is lacking. Here, we analyze genomes, transcriptomes, and methylomes from 943 individuals across 27 tissues, identifying 473 switch-like genes. The identified genes are enriched for associations with cancers and immune, metabolic, and skin diseases. Only 40 (8.5%) switch-like genes show genetically controlled switch-like expression in all tissues, i.e., universally switch-like expression. The rest show switch-like expression in specific tissues. Methylation analysis suggests that genetically driven epigenetic silencing explains the universally switch-like pattern, whereas hormone-driven epigenetic modification likely underlies the tissue-specific pattern. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, driven by tissue-specific master regulators. In the vagina, we identified seven concordantly switched-off genes linked to vaginal atrophy in females. Experimental analysis of vaginal tissues shows that low estrogen levels lead to decreased epithelial thickness and ALOX12 expression. We propose that switched-off driver genes in basal and parabasal epithelia suppress cell proliferation, leading to epithelial thinning and vaginal atrophy. Our findings underscore the implications of switch-like genes for diagnostic and personalized therapeutic applications.