One reason for the current crisis in antibiotic development is the low return on investment, which is intrinsic to anti-infective drug development. Despite this, smaller pharmaceutical companies are attempting to address the medical need for new antibiotics. Natural products have played a major role in antibiotic drug discovery since 1941 when penicillin was introduced to the market, and currently natural products are again the most important source for promising drug candidates. This review discusses novel methods and technologies that will increase the success rate for identifying novel antibiotics from natural sources.