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Mcm4 (minichromosome maintenance–deficient 4 homolog) encodes a subunit of the MCM2-7 complex (also known as MCM2–MCM7), the replication licensing factor and presumptive replicative helicase. Here, we report that the mouse chromosome instability mutation Chaos3 (chromosome aberrations occurring spontaneously 3), isolated in a forward genetic screen, is a viable allele of Mcm4. Mcm4^Chaos3 encodes a change in an evolutionarily invariant amino acid (F345I), producing an apparently destabilized MCM4. Saccharomyces cerevisiae strains that we engineered to contain a corresponding allele (resulting in an F391I change) showed a classical minichromosome loss phenotype. Whereas homozygosity for a disrupted Mcm4 allele (Mcm4⁻) caused preimplantation lethality, Mcm^Chaos3/− embryos died late in gestation, indicating that Mcm4^Chaos3 is hypomorphic. Mutant embryonic fibroblasts were …