The past century of chemotherapy has shown that resistance to antibiotics generally emerges in the clinic rapidly after their introduction for treatment of infectious disease. Furthermore, we know that for antibiotics of natural origin that resistance has co-evolved with their biosynthesis. Antibiotic producers and other bacteria therefore have developed an innate ability to overcome antibiotics; collectively termed the Resistome. What drives this process and what are the molecular origins of resistance? The answers may lie in the diversity of environmental chemicals that are produced by living organisms. Indeed, the genome sequences of microorganisms reveal genetic counterparts to bioactive compounds of diverse structure and function. The selective pressure of bioactive molecules therefore has primed the evolution of the Resistome and provides a challenge for the development of new antibiotics that are not susceptible to resistance.