Genomic instability is a significant challenge in early mammalian development and a cause for developmental failure and abnormalities, particularly in humans. Here, we review our knowledge and explore its significance of genome instability in early embryos across multiple mammalian species, including humans, rhesus macaques, mice, bovines, equines, and porcine. All these species but mice share one feature: frequent chromosomal aberrations, aneuploidy, and developmental failure. We discuss the impact of genome instability on embryonic development, the applicability of gene editing using Cas9, and potential evolutionary implications. We also explore the role of germ cell and early embryo mutations and the bottleneck effect in mammals in comparison to lower vertebrates. Understanding genome stability in mammalian embryos can contribute to our understanding of genetic variation in development and evolution.