The mammalian immune system is required for life. It is a complex system that detects and destroys foreign bacterial, viral and fungal microbe invaders and involves many different types of immune cells and chemical messengers. Its interactions with microbes are highly focused on certain common molecules found on all microbes, primarily bacteria, viruses and fungi. Many harmless but essential microbes play important beneficial roles on and within the human body and in all ecosystems on earth, yet they appear to thrive in the midst of an active immune system that is poised to destroy them. Since there was no death in the Garden of Eden, and therefore no disease-causing microbes, our understanding of both the antimicrobial actions of the immune system and its ability to tolerate good microbes may give us clues to how the immune system operated in the primeval garden.