The human race, like all macrobiological life, evolved in a sea of microbes. There was no way to keep the bacterial and archaeal hoards at bay, so instead life evolved mechanisms to live with these invaders. The immune system was refined over millions of years to control our interaction with the microbial world, and even to use it as a mechanism of defense, food processing, and vitamin production. The immune system and the microbiome have shaped each other in extraordinarily elaborate and intricate ways. Here we will discuss some of the recent evidence highlighting these mechanisms of interaction. We will also discuss how the last 150 years, have started to disturb the delicate balance of the immune-microbe equilibrium. As our natural ecosystem has been restricted to the built environment, especially in the developed world, where an average of 90% of our lives take place indoors, our exposure to the microbial world has been corrupted. Modern buildings are equipped with surfaces and environmental systems designed to reduce the potential for microbial life to flourish. This fundamental shift in our lifestyle is likely impacting the development and function of our immune systems in ways that we are only beginning to understand.