Allegorically, American healthcare and research landscapes are fields of silos, often failing to cultivate products which adequately serve patients or fulfill the potential to advance human biologic science. Interactions, or lack thereof, among the component entities have not resulted in a whole greater than the sum of their parts. Yet, perturbations within one component can reverberate across systems with unintended consequences, or, perhaps more typically, with ignorance of consequences. Indeed, the American health care enterprise is an astounding array of disunited factors and forces including diverse populations, geography, economics, government, the private sector, healthcare providers, researchers, hospital and outpatient systems, and universities, often forced into unequal and haphazard partnerships. Clinical research is a particularly fragile network of silos. It is becoming increasingly more vulnerable because of mounting pressures within the healthcare industry and research community, including reimbursement, regulatory policies, stagnation (or worse) of the federal budget, allocation of physician time and resources, and impending shortage of healthcare personnel. The historic undervaluation of clinical research is exemplified by the sizeable voluntary effort required by physicians to enroll patients, the philanthropic support that must supplement many clinical research programs, and the second-tier status allocated to clinical investigators by university leadership. There are also conflicting policies within government, such as the recent discussions within Centers for Medicare and Medicaid Services to change its coverage policy for Medicare patients on clinical trials (Decision Memo for Clinical Trial Policy). 1 Ironically, the turmoil affecting clinical research within the American healthcare system comes at a time when the potential to unmask some of the complexities of human tumor biology has never been greater. The growing national emphasis supporting evidencebased medicine, quality initiatives, and cost containment mandates the discovery of more links between biology and treatment efficacy. In this issue of the Journal of Clinical Oncology, Kopetz et al evaluate lost opportunities and obstacles hindering the development of new agents for metastatic colorectal cancer—an analysis that can apply to cancer clinical research in general. In their systematic review of active clinical trials in advanced or metastatic colorectal cancer, the authors report that the majority of the trials recruited previouslyuntreated metastatic colorectal cancer patients. Investigated agents that were approved by the US Food and Drug Administration (FDA) for colorectal cancer were used in 53% of trials (representing 81% of the 21,409 patients planned for enrollment). The majority were phase I/II trials (79% representing 33% of the total patients), most trials were initiated since 2005 (66%), and only 13% of trials employed an enrichment trial design, accounting for just 2.9% of the patients planned for enrollment. It appeared that only 8% included tumor biomarkers in an enrichment trial design, representing just 1.7% of the planned trial population of patients. The primary sponsors of the trials included the US Government or cooperative groups, industry, academia, or non-US government (19%, 23%, 42%, and 17% of the trials, respectively, and 17%, 36%, 15%, and 32%, respectively, of the planned patient enrollment). The authors emphasize the persistence of the empiric trial design to investigate antineoplastic agents; a methodology in contradistinction to the FDA Critical Path Initiative. This FDA report emphasizes that for new biomedical science to advance, it will take a united effort on the part of patients, industry, academia, and government. The development of a host of integrated approaches will be essential, including predictive tools to identify candidate agents for additional investigation, animal models of human disease, statistical methodology, scientific instruments and tests, and new biomarkers and diagnostic devices to better establish treatment efficacy for individual patients. To reverse the alarming trend of the massive investment in biomedical research resulting in progressively fewer new medical therapies entering the market, the FDA’s Critical Path must be implemented with the cooperation of all stakeholders. As emphasized by the FDA, the initiation of the National Critical Path will require appropriate infrastructure that can succeed in modernizing product regulation; development of genomic, proteomic, and metabolomic technologies that can lead to individualized or personalized medicine; promotion of innovative trial design; development of bioinformatics to create new models to analyze biologic data; and integration of new imaging. New models need to be developed for training the next generation of clinical trialists equipped to embrace the component stakeholders and to harmonize the laboratory and clinical sciences to more fully distinguish the human tumor biology that can promote highly specific product development. Barriers to optimal clinical research productivity have been outlined over the years, often focusing on the physician as a consistent barrier, as well as regulatory and funding limitations. More recently, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 12 APRIL 2