Microbes colonizing and/or infecting chronic wounds undoubtedly play a major and interactive role in impaired healing, especially in amplifying and perpetuating the host innate immune response. The development of molecular techniques to identify and quantify microbial organisms has revolutionized our view of the microbial world. These less-biased, high throughput methods greatly enable investigations regarding host-microbe interactions in the chronic wound environment. This review focuses on the mounting evidence implicating microbes and excessive inflammation in chronic wounds, as well as the challenges associated with understanding how microbes modulate wound healing and the innate immune response.