In the 75 years since the widespread use of antibiotics began, they have become a pillar of modern medicine, affecting every area of practice. Antibiotic use in patients ranges from those who are seriously, ill, to those with mild illnesses for which treatment benefit is not clear. Such use is based on the belief that the immediate side-effects are generally mild and that long-term effects are rare. Antibiotics are taken more than 70 billion times annually, or more than 10 pills for every person on Earth each year. With such broad use of powerful agents, could there be unexpected consequences? Antibiotics are dosed to suppress or kill bacterial pathogens, but their effects against our residential bacteria (microbiome) was essentially not considered until recently. I have hypothesized that there have been shifts in human micro-ecology due to their widespread high-dose uses in by now up to five human generations, and that these have clinical consequences. We have well-recognized one of these: the emergence of antibiotic resistance. But this likely is only the tip of the iceberg of micro-ecological change. The iceberg’s body, below the level of detection, is the effects on the human microbiome. There is increasing evidence of effects on metabolism, immunity and cognition, which I believe are fuelling the modern plagues including: obesity, asthma, Type 1 diabetes, inflammatory bowel disease, autism, and certain forms of neoplasia. My lab has been conducting experiments that address these questions. In animal models, we have shown that antibiotic-induced perturbations of the early-life microbiome are causal for experimental obesity, allergy, asthma, T1D, colitis, and increased susceptibility to infection. We must recognize that antibiotics are a two-edged sword; as such, we must use them more wisely, and consider ways to restore our depleted microbiota.