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It has long been known that Saccharomyces cerevisiae homoserine kinase (thr1) and threonine synthase (thr4) mutants, deficient in the final steps in threonine biosynthesis, have many deleterious phenotypes. In this issue, Kingsbury and McCusker (p. 729–737) show that S. cerevisiae thr1Δ and thr4Δ strains and Candida albicans thr1Δ strains rapidly die in serum, which has a naturally low threonine concentration. Cell death does not result from threonine auxotrophy per se but rather from the accumulation of a threonine biosynthetic intermediate, homoserine, that acts as a threonine analog (p. 717–728). Surprisingly, homoserine toxicity requires proteasome activity. These studies validate Thr1 and Thr4 as promising antimicrobial drug targets and provide a foundation for future studies that connect the proteasome and amino acid analog toxicity.