Recommendations in the "Guideline for Prevention of Surgical Site Infection, 1999" were based on experts' selective interpretation of the scientific evidence. Effective 2009, the U.S. Centers for Disease Control and Prevention (CDC) and its Healthcare Infection Control Practices Advisory Committee (HICPAC) updated their guideline development process. This is a narrative summary of the updated process focusing on key changes and challenges specific to the Guideline for Prevention of Surgical Site Infection. The guideline development process now incorporates evidence-based methodology and provides explicit links between the evidence and the recommendations using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. There is also participation by professional surgical societies, an updated guideline structure (core and procedure-specific sections), additional planned related manuscripts (introductions to the guideline and research opportunities), and new proposed venues for publication. The new CDC and HICPAC "Guideline for the Prevention of Surgical Site Infection" represents a substantial advancement from recommendations for infection control practices based on expert opinion to evidence-based practices. The new structure is meant to facilitate future updates, in particular, those addressing specialty or procedure-specific surgical site infection prevention questions. Increased presence by the surgical community through the professional surgical societies' engagement in the guideline development process, lead authorship of related manuscripts, and proposed publication in the surgical literature not only increase adherence by the surgical community, but also promote an ongoing collaboration with public health and other partners in a multidisciplinary approach to SSI prevention.