Self-replicating genetic material presumably provided the architecture necessary for generating the last universal ancestor of all nucleic-acid-based life. As biological complexity increased in the billions of years that followed, the same genetic material also morphed into a wide spectrum of viruses and other parasitic genetic elements. The resulting struggle for existence drove the evolution of host defenses, giving rise to a perpetual arms race. This Perspective summarizes the antiviral mechanisms evident across the tree of life, discussing each in their evolutionary context to postulate how the coevolution of host and pathogen shaped the cellular antiviral defenses we know today.