Antibiotic resistance has been an ongoing challenge that has emerged almost immediately after the initial discovery of antibiotics and requires the development of innovative new antibiotics and antibiotic combinations that can effectively mitigate the development of resistance. More than 35,000 people die each year from antibiotic resistant infections in just the United States. This signifies the importance of identifying other alternatives to antibiotics for which resistance has developed. Virtually, all currently used antibiotics can trace their genesis to soil derived bacteria and fungi. The bacteria and fungi involved in symbiosis is an area that still remains widely unexplored for the discovery and development of new antibiotics. This brief review focuses on the challenges and opportunities in the application of symbiotic microbes and also provides an interesting platform that links natural product chemistry with evolutionary biology and ecology.