Lean Six Sigma, in various forms, has been used widely in many Fortune 500 companies. Motorola, General Electric, Sony, American Express, and Bechtel all use Six Sigma to improve quality and performance. While the impact of this methodology has been documented extensively by the press in manufacturing and transactional settings, less evidence is available regarding its utility in health care environments. Mount Sinai Medical Center initiated a Six Sigma program in 2000 to determine its applicability and value in a large academic medical center. This article discusses Mount Sinai Medical Center's experience adapting this methodology to improve both patient care and business processes and outcomes. We present an overview of Six Sigma, and offer examples of projects undertaken using this data-driven approach to performance improvement. Lastly, the article provides insights and lessons learned regarding this organization-wide experience.