The benefits of applying comparative effectiveness research (CER) strategies to the management of cancer are important. As the incidence of cancer increases both in the United States and worldwide, accurate analysis of which tests and treatments should be applied in which situations is critical, both in terms of measurable and meaningful clinical outcomes and health care costs. In the last 20 years alone, multiple controversies have arisen in the diagnosis and treatment of primary and metastatic tumors of the liver, making the management of liver malignancies a prime example of CER. Contributing factors to the development of these controversies include improvements in molecular characterization of these diseases and technological advances in surgery and radiology. The relative speed of these advances has outpaced data from clinical trials, in turn making robust data to inform clinical practice lacking. Indeed, many of the current treatment recommendations for the management of liver malignancies are based primarily on retrospective data. We herein review select CER issues concerning select decision-making topics in the management of liver malignancies.