Transmyocardial laser revascularization (TMR) with the CO2 laser (PLC Medical Systems, Inc., Franklin, MA) appears to improve the quality of life and event-free survival of end-stage coronary artery disease patients. Application of this technology prior to clinical instability, along with diligent anesthetic support, careful patient selection, and perioperative management, are essential to a successful outcome. Rush-Presbyterian-St. Luke's Medical Center became the fifth clinical site to investigate TMR under Phase II and Phase III U.S. Food and Drug Administration (FDA) protocols. This clinical experience includes a total of seventy-nine patients, of whom sixty-three had sole TMR utilizing a minimally invasive approach on the beating heart. Lessons learned, to optimize patient selection and operative- and postoperative management, will be delineated and the future direction of TMR will be discussed.