Despite significant improvements in peri-operative care, surgical site infections (SSIs) remain an important contributor to morbidity, cost, and death. The human gastrointestinal tract is a complex microenvironment linking host cells and the indigenous microflora or “microbiome,” creating a “super-organism” that engages in macro-nutrient and micro-nutrient extraction for the host while serving as a barrier to toxins and other detrimental bacterial end-products. Maintaining a healthy microbiome in the peri-operative period may enable control of multi-drug resistance (MDR) organisms, whereas use of antibiotics simply resets the dysbiotic relation by eliminating multiple strains of bacteria. Such loss of microbial diversity or abundance can slow wound healing. Use of pro-biotics to prevent infection has been evaluated in several studies, but their utility is not yet clear. There is a clear need for randomized trials to draw firm conclusions about their efficacy and to make clinical recommendations.