There are important challenges in the application of using operations research (OR) and cost-effectiveness analysis (CEA) in the real world that highlight the great divide between academic research and practical application. The difficulty is magnified in cancer. Nevertheless, the potential for CEA to inform policy decisions is also great. The best estimate of a new drug’s cost-effectiveness is not knowledge for knowledge’s sake; this type of information is the foundation of accountability for the hundreds of millions of dollars being spent. In 2007, Cancer Care Ontario (CCO) established Canada’s first in-house Pharmacoeconomics Research Unit comprised of independent researchers. This chapter reviews the initial years of the Unit at CCO after briefly describing Canada’s cancer drug funding landscape. The chapter concludes by sharing lessons from the Pharmacoeconomics Research Unit’s experience and pointing out directions for future research aimed at reaching decision makers in the real world.