The clinical introduction of antibiotics has dramatically affected our approach to treating infectious diseases. Surprisingly, soil-dwelling bacteria have played a central role in this undertaking. Approximately two-thirds of all known antibiotics are synthesized as natural products of the bacterial class Actinomycetes, many of which belong to the Streptomyces genus. Evolving in an environment of antibiotic production, these remarkably resilient bacteria must develop diverse ways to survive the toxic antimicrobial compounds synthesized around them. As a result, they have evolved robust resistance to diverse classes of antibiotics, mechanisms that are often homologous to those identified in clinical pathogens. Thus their resistance mechanisms may help us glimpse into the future of clinical resistance to antibiotics, serving as an early-warning system of resistance that might emerge clinically.