It has long been appreciated that a multitude of bacteria, fungi and viruses colonise our skin, collectively termed the skin microbiome. Only recently have technological advances allowed comprehensive profiling of the wide diversity of the skin microbiome across homeostasis and disease. A picture is emerging where resident commensal microbes may confer significant beneficial effects on skin health while pathogenic bacteria are currently being linked to numerous skin diseases. Surprisingly, despite bacterial wound colonisation and infection being a major clinical concern mechanistic understanding of host-microbiome interactions during skin wound repair remains poor. Here we provide direct evidence that the microbiome signature of human chronic wounds strongly predicts healing outcome. Moreover, our mechanistic studies have identified a potential mediator, the pattern recognition receptor, Nod2. Nod2 is downregulated in wounds from elderly humans and Nod2 null mice display a pronounced healing delay. We hypothesised that this delayed healing was the result of host microbiome differences. Now for the first time we show that Nod2 null mice display major changes in skin/wound microbiome, and an increased total bacterial burden. A mechanistic link is provided by specific alterations to the host innate immune response in nod2 null mice, including changes in the production of specific skin-derived antimicrobial peptides. Collectively, our findings suggest that the skin microbiome plays a major role in wound healing outcome providing substantial new insight into the importance of host-microbiota interactions.